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Journal articles on the topic 'Chromodomain Helicase DNA binding 4 (CHD4)'

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Published: 7 July 2024
Last updated: 7 July 2024

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1

Kolla, Venkatadri, Koumudi Naraparaju, Tiangang Zhuang, Mayumi Higashi, Sriharsha Kolla, Gerd A. Blobel, and Garrett M. Brodeur. "The tumour suppressor CHD5 forms a NuRD-type chromatin remodelling complex." Biochemical Journal 468, no. 2 (May 22, 2015): 345–52. http://dx.doi.org/10.1042/bj20150030.

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Chromodomain helicase DNA-binding protein 5 (CHD5) is localized exclusively in nucleus and forms nucleosome remodelling histone deacetylase (NuRD) complex with metastasis-associated protein (MTA)1/2, GATAD2A, histone deacetylase (HDAC)1/2, retinoblastoma-binding protein (RBBP)4/7 and methyl DNA-binding domain protein (MBD)3. Novel protein associations with CHD5–NuRD may account for the functional differences compared with CHD4–NuRD.
2

Sillibourne, James Edward, Bénédicte Delaval, Sambra Redick, Manisha Sinha, and Stephen John Doxsey. "Chromatin Remodeling Proteins Interact with Pericentrin to Regulate Centrosome Integrity." Molecular Biology of the Cell 18, no. 9 (September 2007): 3667–80. http://dx.doi.org/10.1091/mbc.e06-07-0604.

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Pericentrin is an integral centrosomal component that anchors regulatory and structural molecules to centrosomes. In a yeast two-hybrid screen with pericentrin we identified chromodomain helicase DNA-binding protein 4 (CHD4/Mi2β). CHD4 is part of the multiprotein nucleosome remodeling deacetylase (NuRD) complex. We show that many NuRD components interacted with pericentrin by coimmunoprecipitation and that they localized to centrosomes and midbodies. Overexpression of the pericentrin-binding domain of CHD4 or another family member (CHD3) dissociated pericentrin from centrosomes. Depletion of CHD3, but not CHD4, by RNA interference dissociated pericentrin and γ-tubulin from centrosomes. Microtubule nucleation/organization, cell morphology, and nuclear centration were disrupted in CHD3-depleted cells. Spindles were disorganized, the majority showing a prometaphase-like configuration. Time-lapse imaging revealed mitotic failure before chromosome segregation and cytokinesis failure. We conclude that pericentrin forms complexes with CHD3 and CHD4, but a distinct CHD3–pericentrin complex is required for centrosomal anchoring of pericentrin/γ-tubulin and for centrosome integrity.
3

Lin, Shiaw-Yih, Jing Zhang, and David J.H. Shih. "The Tale of CHD4 in DNA Damage Response and Chemotherapeutic Response." Cancer Research and Cellular Therapeutics 3, no. 1 (July 8, 2019): 01–03. http://dx.doi.org/10.31579/2640-1053/052.

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The chromatin remodeling factor chromodomain helicase DNA-binding protein 4 (CHD4) is a core component of the nucleosome remodeling and deacetylase (NuRD) complex. Due to its important role in DNA damage repair, CHD4 has been identified as a key determinant in cancer progression, stem cell differentiation, and T cell and B cell development. Accumulating evidence has revealed that CHD4 can function in NuRD dependent and independent manner in response to DNA damage. Mutations of CHD4 have been shown to diminish its functions, which indicates that interpretation of its mutations may provide tangible benefit for patients. The expression of CHD4 play a dual role in sensitizing cancer cells to chemotherapeutic agents, which provides new insights into the contribution of CHD4 to tumor biology and new therapeutic avenues.
4

Hagman, James, Carissa Dege, Desiree Straign, Haiqun Jia, Kendra Walton, Kara Lukin, Hong Lei, Thomas Danhorn, and Ann Feeney. "Chromodomain helicase DNA-binding 4 is required for proliferation, distal VH rearrangements and developmental progression of B cell progenitors (HEM1P.221)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 50.4. http://dx.doi.org/10.4049/jimmunol.194.supp.50.4.

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Abstract Chromodomain Helicase DNA-binding protein 4 (CHD4, or Mi-2β) is a catalytic core subunit of Nucleosome Remodeling and Deacetylase (NuRD) complexes, which regulate chromatin structure and transcription in lymphocytes. CHD4 activities include ATP-dependent mobilization of nucleosomes, DNA binding and binding to histone tails. Here, we investigated requirements for CHD4 in B cell development in a mouse model system. We utilized Chd4flox/flox:Cd79a-Cre (Chd4 cko) mice, which inactivate Chd4 genes selectively in early B cell progenitors. These mice confirmed that CHD4 is essential for B lymphopoiesis. Following the loss of CHD4 expression, B cell development is arrested at the pro-B cell stage. Peripheral B220+ cells were nearly absent. To address the basis of the observed developmental arrest, we measured effects of the lack of CHD4 on proliferation and Igh gene rearrangements. CHD4-deficient pro-B cells fail to proliferate in response to IL-7. Furthermore, pro-B cells lacking CHD4 complete proximal VH to DJH rearrangements, but rearrange distal VH segments only rarely. Overall, our data demonstrate that CHD4 and NuRD complexes are essential for multiple aspects of early B cell development, including V(D)J recombination, proliferation and survival of pro-B cells.
5

Chohra, Ilyas, Subhajit Giri, and Brigitte Malgrange. "Generation of a Well-Characterized Homozygous Chromodomain-Helicase-DNA-Binding Protein 4G1003D Mutant hESC Line Using CRISPR/eCas9 (ULIEGEe001-A-1)." International Journal of Molecular Sciences 24, no. 13 (June 23, 2023): 10543. http://dx.doi.org/10.3390/ijms241310543.

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The chromatin remodeler Chromodomain-helicase-DNA-binding protein 4 (CHD4) is crucial for the development of multiple organ systems. Functional mutations of CHD4 have recently been described in a developmental disorder, namely Siffrim-Hitz-Weiss syndrome (SIHIWES). Herein, we have generated a homozygous CHD4G1003D hESC line (WAe025-A-1) using CRISPR/eCas9-based gene editing in the WA-25 hESC line. The edited hESC line maintains normal karyotype, pluripotency, and ability to differentiate into three germ layers. This cell line will be a valuable resource for studying the functional role of CHD4 during the development and disease modeling of SIHIWES in vitro.
6

Larsen, Dorthe Helena, Catherine Poinsignon, Thorkell Gudjonsson, Christoffel Dinant, Mark R. Payne, Flurina J. Hari, Jannie M. Rendtlew Danielsen, et al. "The chromatin-remodeling factor CHD4 coordinates signaling and repair after DNA damage." Journal of Cell Biology 190, no. 5 (August 30, 2010): 731–40. http://dx.doi.org/10.1083/jcb.200912135.

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In response to ionizing radiation (IR), cells delay cell cycle progression and activate DNA repair. Both processes are vital for genome integrity, but the mechanisms involved in their coordination are not fully understood. In a mass spectrometry screen, we identified the adenosine triphosphate–dependent chromatin-remodeling protein CHD4 (chromodomain helicase DNA-binding protein 4) as a factor that becomes transiently immobilized on chromatin after IR. Knockdown of CHD4 triggers enhanced Cdc25A degradation and p21Cip1 accumulation, which lead to more pronounced cyclin-dependent kinase inhibition and extended cell cycle delay. At DNA double-strand breaks, depletion of CHD4 disrupts the chromatin response at the level of the RNF168 ubiquitin ligase, which in turn impairs local ubiquitylation and BRCA1 assembly. These cell cycle and chromatin defects are accompanied by elevated spontaneous and IR-induced DNA breakage, reduced efficiency of DNA repair, and decreased clonogenic survival. Thus, CHD4 emerges as a novel genome caretaker and a factor that facilitates both checkpoint signaling and repair events after DNA damage.
7

Hosokawa, Hiroyuki, Tomoaki Tanaka, Miki Kato, Yuuki Tamaki, and Toshinori Nakayama. "Functionally distinct Gata3/Chd4 complexes coordinately establish Th2 cell identity. (P1340)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 208.13. http://dx.doi.org/10.4049/jimmunol.190.supp.208.13.

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Abstract Gata3 is a GATA family transcription factor that controls differentiation of naïve CD4 T cells into T helper (Th) 2 cells. However, it is unknown how Gata3 simultaneously activates Th2-specific genes while repressing those of other Th lineages. Here we show that Chd4 (chromodomain helicase DNA-binding protein 4) forms a complex with Gata3 in Th2 cells that both activates Th2 cytokine transcription and represses the Th1 cytokine IFNγ. We define a Gata3/Chd4/p300 transcriptional activation complex at the Th2 cytokine loci and a Gata3/Chd4-NuRD repression complex at the Tbx21 locus in Th2 cells. We also demonstrated a physiological role for Chd4 in Th2-dependent inflammation in an in vivo model of asthmatic inflammation. Thus, Gata3/Chd4 forms functionally distinct complexes, which mediate both positive and negative gene regulation to facilitate Th2 cell differentiation.
8

Arends, Tessa, Carissa Dege, Alexandra Bortnick, Thomas Danhorn, Jennifer R. Knapp, Haiqun Jia, Laura Harmacek, et al. "CHD4 is essential for transcriptional repression and lineage progression in B lymphopoiesis." Proceedings of the National Academy of Sciences 116, no. 22 (May 13, 2019): 10927–36. http://dx.doi.org/10.1073/pnas.1821301116.

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Cell lineage specification is a tightly regulated process that is dependent on appropriate expression of lineage and developmental stage-specific transcriptional programs. Here, we show that Chromodomain Helicase DNA-binding protein 4 (CHD4), a major ATPase/helicase subunit of Nucleosome Remodeling and Deacetylase Complexes (NuRD) in lymphocytes, is essential for specification of the early B cell lineage transcriptional program. In the absence of CHD4 in B cell progenitors in vivo, development of these cells is arrested at an early pro-B-like stage that is unresponsive to IL-7 receptor signaling and unable to efficiently complete V(D)J rearrangements at Igh loci. Our studies confirm that chromatin accessibility and transcription of thousands of gene loci are controlled dynamically by CHD4 during early B cell development. Strikingly, CHD4-deficient pro-B cells express transcripts of many non-B cell lineage genes, including genes that are characteristic of other hematopoietic lineages, neuronal cells, and the CNS, lung, pancreas, and other cell types. We conclude that CHD4 inhibits inappropriate transcription in pro-B cells. Together, our data demonstrate the importance of CHD4 in establishing and maintaining an appropriate transcriptome in early B lymphopoiesis via chromatin accessibility.
9

O’Shaughnessy, Aoife, and Brian Hendrich. "CHD4 in the DNA-damage response and cell cycle progression: not so NuRDy now." Biochemical Society Transactions 41, no. 3 (May 23, 2013): 777–82. http://dx.doi.org/10.1042/bst20130027.

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The CHD4 (chromodomain-helicase-DNA-binding 4) (or Mi-2β) protein is a founding component of the NuRD (nucleosome remodelling and deacetylation) complex. NuRD has long been known to function in transcriptional regulation, and is conserved throughout the animal and plant kingdoms. In recent years, evidence has steadily accumulated indicating that CHD4 can both function outside of the NuRD complex and also play important roles in cellular processes other than transcriptional regulation. A number of loss-of-function studies have identified important roles for CHD4 in the DNA-damage response and in cell cycle progression through S-phase and into G2. Furthermore, as part of NuRD, it participates in regulating acetylation levels of p53, thereby indirectly regulating the G1/S cell cycle checkpoint. Although CHD4 has a somewhat complicated relationship with the cell cycle, recent evidence indicates that CHD4 may exert some tumour-suppressor functions in human carcinogenesis. CHD4 is a defining member of the NuRD complex, but evidence is accumulating that CHD4 also plays important NuRD-independent roles in the DNA-damage response and cell cycle progression, as well as in transcriptional regulation.
10

Smeenk, Godelieve, Wouter W. Wiegant, Hans Vrolijk, Aldo P. Solari, Albert Pastink, and Haico van Attikum. "The NuRD chromatin–remodeling complex regulates signaling and repair of DNA damage." Journal of Cell Biology 190, no. 5 (August 30, 2010): 741–49. http://dx.doi.org/10.1083/jcb.201001048.

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Cells respond to ionizing radiation (IR)–induced DNA double-strand breaks (DSBs) by orchestrating events that coordinate cell cycle progression and DNA repair. How cells signal and repair DSBs is not yet fully understood. A genome-wide RNA interference screen in Caenorhabditis elegans identified egr-1 as a factor that protects worm cells against IR. The human homologue of egr-1, MTA2 (metastasis-associated protein 2), is a subunit of the nucleosome-remodeling and histone deacetylation (NuRD) chromatin-remodeling complex. We show that knockdown of MTA2 and CHD4 (chromodomain helicase DNA-binding protein 4), the catalytic subunit (adenosine triphosphatase [ATPase]) of NuRD, leads to accumulation of spontaneous DNA damage and increased IR sensitivity. MTA2 and CHD4 accumulate in DSB-containing chromatin tracks generated by laser microirradiation. Directly at DSBs, CHD4 stimulates RNF8/RNF168-dependent formation of ubiquitin conjugates to facilitate the accrual of RNF168 and BRCA1. Finally, we show that CHD4 promotes DSB repair and checkpoint activation in response to IR. Thus, the NuRD chromatin–remodeling complex is a novel regulator of DNA damage responses that orchestrates proper signaling and repair of DSBs.
11

Musselman, Catherine A., Robyn E. Mansfield, Adam L. Garske, Foteini Davrazou, Ann H. Kwan, Samuel S. Oliver, Heather O'Leary, John M. Denu, Joel P. Mackay, and Tatiana G. Kutateladze. "Binding of the CHD4 PHD2 finger to histone H3 is modulated by covalent modifications." Biochemical Journal 423, no. 2 (September 25, 2009): 179–87. http://dx.doi.org/10.1042/bj20090870.

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CHD4 (chromodomain helicase DNA-binding protein 4) ATPase is a major subunit of the repressive NuRD (nucleosome remodelling and deacetylase) complex, which is involved in transcriptional regulation and development. CHD4 contains two PHD (plant homeodomain) fingers of unknown function. Here we show that the second PHD finger (PHD2) of CHD4 recognizes the N-terminus of histone H3 and that this interaction is facilitated by acetylation or methylation of Lys9 (H3K9ac and H3K9me respectively) but is inhibited by methylation of Lys4 (H3K4me) or acetylation of Ala1 (H3A1ac). An 18 μM binding affinity toward unmodified H3 rises to 0.6 μM for H3K9ac and to 0.9 μM for H3K9me3, whereas it drops to 2.0 mM for H3K4me3, as measured by tryptophan fluorescence and NMR. A peptide library screen further shows that phosphorylation of Thr3, Thr6 or Ser10 abolishes this interaction. A model of the PHD2–H3 complex, generated using a combination of NMR, data-driven docking and mutagenesis data, reveals an elongated site on the PHD2 surface where the H3 peptide is bound. Together our findings suggest that the PHD2 finger plays a role in targeting of the CHD4/NuRD complex to chromatin.
12

Pratheeshkumar, Poyil, Abdul K. Siraj, Sasidharan Padmaja Divya, Sandeep Kumar Parvathareddy, Khadija Alobaisi, Saif S. Al-Sobhi, Fouad Al-Dayel, and Khawla S. Al-Kuraya. "CHD4 Predicts Aggressiveness in PTC Patients and Promotes Cancer Stemness and EMT in PTC Cells." International Journal of Molecular Sciences 22, no. 2 (January 6, 2021): 504. http://dx.doi.org/10.3390/ijms22020504.

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Chromodomain-helicase-DNA-binding protein 4 (CHD4), a core subunit of the nucleosome remodeling and deacetylation (NuRD) complex is highly expressed in several cancers. However, its role in the pathogenesis and progression of papillary thyroid carcinoma (PTC) has not been investigated. We investigated the prognostic significance of CHD4 in a large cohort of Middle Eastern PTC patients and explored the functional role of CHD4 in regulating cancer stemness and EMT in PTC cells. CHD4 overexpression was observed in 45.3% (650/1436) of PTCs, and was associated with aggressive clinico-pathological parameters and worse outcome. Functional analysis using PTC cell lines showed that forced expression of CHD4 promoted cell proliferation, spheroid growth, migration, invasion and progression of epithelial to mesenchymal transition (EMT) in PTC cells whereas its knockdown reversed the effect. Methylation of E-cadherin was associated with loss of expression in CHD4 expressing cells, while CHD4 depletion reactivated E-cadherin expression. Most importantly, knockdown of mesenchymal transcriptional factors, Snail1 or Zeb1, attenuated the spheroid growth in CHD4 expressing PTC cells, showing a potential link between EMT activation and stemness maintenance in PTC. These findings suggest that CHD4 might be a promising therapeutic target in the treatment of patients with an aggressive subtype of PTC.
13

Hagman, James R., Tessa Arends, Curtis Laborda, Jennifer R. Knapp, Laura Harmacek, and Brian P. O’Connor. "Chromodomain helicase DNA‐binding 4 (CHD4) regulates early B cell identity and V(D)J recombination*." Immunological Reviews 305, no. 1 (December 20, 2021): 29–42. http://dx.doi.org/10.1111/imr.13054.

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14

Qi, Wenjing, Hongyu Chen, Ting Xiao, Ruoxi Wang, Ting Li, Liping Han, and Xianlu Zeng. "Acetyltransferase p300 collaborates with chromodomain helicase DNA-binding protein 4 (CHD4) to facilitate DNA double-strand break repair." Mutagenesis 31, no. 2 (November 6, 2015): 193–203. http://dx.doi.org/10.1093/mutage/gev075.

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15

Oyama, Yoshiko, Shogo Shigeta, Hideki Tokunaga, Keita Tsuji, Masumi Ishibashi, Yusuke Shibuya, Muneaki Shimada, Jun Yasuda, and Nobuo Yaegashi. "CHD4 regulates platinum sensitivity through MDR1 expression in ovarian cancer: A potential role of CHD4 inhibition as a combination therapy with platinum agents." PLOS ONE 16, no. 6 (June 23, 2021): e0251079. http://dx.doi.org/10.1371/journal.pone.0251079.

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Platinum sensitivity is an important prognostic factor in patients with ovarian cancer. Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a core member of the nucleosome remodeling and deacetylase complex, which functions as a chromatin remodeler. Emerging evidence indicates that CHD4 could be a potential therapeutic target for cancer therapy. The purpose of this study was to clarify the role of CHD4 in ovarian cancer and investigate its therapeutic potential focusing on platinum sensitivity. In an analysis of the Cancer Genome Atlas ovarian cancer dataset, CHD4 gene amplification was associated with worse overall survival. CHD4 mRNA expression was significantly higher in platinum-resistant samples in a subsequent clinical sample analysis, suggesting that CHD4 overexpression conferred platinum resistance to ovarian cancer cells, resulting in poor patient survival. In concordance with these findings, CHD4 knockdown enhanced the induction of apoptosis mediated by cisplatin in ovarian cancer cells TOV21G and increased cisplatin sensitivity in multiple ovarian cancer cells derived from different subtypes. However, CHD4 knockdown did not affect the expression of RAD51 or p21, the known targets of CHD4 in other cancer types that can modulate platinum sensitivity. Knockdown and overexpression assays revealed that CHD4 positively regulated the expression of multi-drug transporter MDR1 and its coding protein p-glycoprotein. In addition, a first-in-class CHD4/SMARCA5 inhibitor ED2-AD101 showed synergistic interactions with cisplatin. Our findings suggest that CHD4 mediates platinum sensitivity by modulating MDR1 expression in ovarian cancer. Further, CHD4 suppression has a potential to be a novel therapeutic strategy in combination with platinum agents.
16

Hancock, Wayne W., Liqing Wang, Martina Minisini, Eros di Giorgio, Ivan Babic, and Elmar Nurmemmedov. "Abstract 2655: Unexpected role of the NuRD component, Chd4, in Foxp3+ Treg cells and its relevance to tumor immunotherapy." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2655. http://dx.doi.org/10.1158/1538-7445.am2024-2655.

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Abstract We are investigating basic questions like why do Foxp3+ T-regulatory (Treg) cells have at least 3 nuclear complexes involving Hdac1 and Hdac2 (CoREST, Sin3, NuRD), and how can the inhibitory effects of Foxp3+ Tregs on host anti-tumor immune responses be targeted therapeutically? Here, we report on the immune functions of chromodomain-helicase-DNA-binding protein 4 (Chd4), a key enzyme of the nucleosome remodeling and deacetylase complex (NuRD) complex. TCGA analysis showed increased Chd4 expression and Foxp3+ Tregs within lung tumors, leading us to assess the effects of conditional gene deletion within Foxp3+ murine Tregs. Chd4 knockout led to systemic autoimmunity and death of mice within 3 weeks of life and RNAseq studies showed Chd4 loss led to derepression of ~1400 genes and repression of >700 further genes resulting in a Treg signature markedly different from conditional deletion of Hdac1, Hdac2 or Mbd2 in Treg cells. Chd4 is an intrinsically disordered therapeutic target without a defined structure outside its physiological cell environment. To date, no specific inhibitors targeting Chd4 have been developed. We have identified Ch41, a novel and potent inhibitor of Chd4, using a novel cellular target engagement platform. Transcriptomic and mass-spec investigations showed that Ch41 impaired thymic Treg function and iTreg development, led to decreased CNS2 demethylation within the Foxp3 locus, and significantly impaired growth of lung tumors and hepatocellular carcinomas in immunocompetent but not in immunodeficient C57BL/6 mice (p<0.01). Following Chd4 inhibitor therapy, intratumoral conventional T cells had increased activation and cytokine production (IL-2, IFN-g) compared to intratumoral T cells in control tumor-bearing mice but, perhaps unexpectedly, treated mice did not show histologic or biochemical evidence of autoimmunity. We conclude that while tumor associated Tregs have unique properties that include their increased suppressive activity compared to non-tumor associated Treg cells, they are also more susceptible than the latter and conventional T cells to newly developed therapeutic interventions, including targeting of the Chd4 chromodomain of the NuRD complex. Citation Format: Wayne W. Hancock, Liqing Wang, Martina Minisini, Eros di Giorgio, Ivan Babic, Elmar Nurmemmedov. Unexpected role of the NuRD component, Chd4, in Foxp3+ Treg cells and its relevance to tumor immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2655.
17

Da Silva, Jorge Diogo, Natália Oliva-Teles, Nataliya Tkachenko, Joana Fino, Mariana Marques, Ana Maria Fortuna, and Dezso David. "A Novel Frameshift CHD4 Variant Leading to Sifrim-Hitz-Weiss Syndrome in a Proband with a Subclinical Familial t(17;19) and a Large Dup(2)(q14.3q21.1)." Biomedicines 11, no. 1 (December 21, 2022): 12. http://dx.doi.org/10.3390/biomedicines11010012.

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The genetic complexity of neurodevelopmental disorders (NDD), combined with a heterogeneous clinical presentation, makes accurate assessment of their molecular bases and pathogenic mechanisms challenging. Our purpose is to reveal the pathogenic variant underlying a complex NDD through identification of the “full” spectrum of structural genomic and genetic variants. Therefore, clinical phenotyping and identification of variants by genome and exome sequencing, together with comprehensive assessment of these and affected candidate genes, were carried out. A maternally-inherited familial translocation [t(17;19)(p13.1;p13.3)mat] disrupting the GSG1 like 2 gene (GSG1L2), a 3.2 Mb dup(2)(q14.3q21.1) encompassing the autosomal dominant OMIM phenotype-associated PROC and HS6ST1 gene, and a novel frameshift c.4442del, p.(Gly1481Valfs*21) variant within exon 30 of the Chromodomain helicase DNA binding protein 4 (CHD4) have been identified. Considering the pathogenic potential of each variant and the proband’s phenotype, we conclude that this case basically fits the Sifrim–Hitz–Weiss syndrome or CHD4-associated neurodevelopmental phenotype. Finally, our data highlight the need for identification of the “full” spectrum of structural genomic and genetic variants and of reverse comparative phenotyping, including unrelated patients with variants in same genes, for improved genomic healthcare of patients with NDD.
18

Yamada, Miki, Noriko Sato, Shinobu Ikeda, Tomio Arai, Motoji Sawabe, Seijiro Mori, Yoshiji Yamada, Masaaki Muramatsu, and Masashi Tanaka. "Association of the chromodomain helicase DNA-binding protein 4 (CHD4) missense variation p.D140E with cancer: Potential interaction with smoking." Genes, Chromosomes and Cancer 54, no. 2 (November 19, 2014): 122–28. http://dx.doi.org/10.1002/gcc.22227.

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Denson, Aspin, Matt Parker, WAGNER DIAS, Halyna Fedosyuk, Maria Villar-Lecumberri, Jeff Thompson, Harmony Saunders, and Chad Slawson. "Abstract 1049 O-GlcNAc crosslinking of Chromodomain Helicase DNA Binding Protein 4 (CHD4) reveals novel functions for the Nucleosome Chromatin Remodeling Complex." Journal of Biological Chemistry 300, no. 3 (March 2024): 106818. http://dx.doi.org/10.1016/j.jbc.2024.106818.

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Pan, Mei-Ren, Hui-Ju Hsieh, Hui Dai, Wen-Chun Hung, Kaiyi Li, Guang Peng, and Shiaw-Yih Lin. "Chromodomain Helicase DNA-binding Protein 4 (CHD4) Regulates Homologous Recombination DNA Repair, and Its Deficiency Sensitizes Cells to Poly(ADP-ribose) Polymerase (PARP) Inhibitor Treatment." Journal of Biological Chemistry 287, no. 9 (January 4, 2012): 6764–72. http://dx.doi.org/10.1074/jbc.m111.287037.

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21

Singh, Ajeet P., Julie F. Foley, Mark Rubino, Michael C. Boyle, Arpit Tandon, Ruchir Shah, and Trevor K. Archer. "Brg1 Enables Rapid Growth of the Early Embryo by Suppressing Genes That Regulate Apoptosis and Cell Growth Arrest." Molecular and Cellular Biology 36, no. 15 (May 16, 2016): 1990–2010. http://dx.doi.org/10.1128/mcb.01101-15.

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SWI/SNF (switching/sucrose nonfermenting)-dependent chromatin remodeling establishes coordinated gene expression programs during development, yet important functional details remain to be elucidated. We show that the Brg1 (Brahma-related gene 1; Smarca4) ATPase is globally expressed at high levels during postimplantation development and its conditional ablation, beginning at gastrulation, results in increased apoptosis, growth retardation, and, ultimately, embryonic death. Global gene expression analysis revealed that genes upregulated inRosa26CreERT2;Brg1flox/floxembryos (here referred to asBrg1d/dembryos to describe embryos with deletion of theBrg1flox/floxalleles) negatively regulate cell cycle progression and cell growth. In addition, the p53 (Trp53) protein, which is virtually undetectable in early wild-type embryos, accumulated in theBrg1d/dembryos and activated the p53-dependent pathways. Using P19 cells, we show that Brg1 and CHD4 (chromodomain helicase DNA binding protein 4) coordinate to control target gene expression. Both proteins physically interact and show a substantial overlap of binding sites at chromatin-accessible regions adjacent to genes differentially expressed in theBrg1d/dembryos. Specifically, Brg1 deficiency results in reduced levels of the repressive histone H3 lysine K27 trimethylation (H3K27me3) histone mark and an increase in the amount of open chromatin at the regulatory region of thep53andp21(Cdkn1a) genes. These results provide insights into the mechanisms by which Brg1 functions, which is in part via the p53 program, to constrain gene expression and facilitate rapid embryonic growth.
22

Guo, Tingting, Daofeng Wang, Jingjing Fang, Jinfeng Zhao, Shoujiang Yuan, Langtao Xiao, and Xueyong Li. "Mutations in the Rice OsCHR4 Gene, Encoding a CHD3 Family Chromatin Remodeler, Induce Narrow and Rolled Leaves with Increased Cuticular Wax." International Journal of Molecular Sciences 20, no. 10 (May 25, 2019): 2567. http://dx.doi.org/10.3390/ijms20102567.

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Leaf blade width, curvature, and cuticular wax are important agronomic traits of rice. Here, we report the rice Oschr4-5 mutant characterized by pleiotropic phenotypes, including narrow and rolled leaves, enhanced cuticular wax deposition and reduced plant height and tiller number. The reduced leaf width is caused by a reduced number of longitudinal veins and increased auxin content. The cuticular wax content was significantly higher in the Oschr4-5 mutant, resulting in reduced water loss rate and enhanced drought tolerance. Molecular characterization reveals that a single-base deletion results in a frame-shift mutation from the second chromodomain of OsCHR4, a CHD3 (chromodomain helicase DNA-binding) family chromatin remodeler, in the Oschr4-5 mutant. Expressions of seven wax biosynthesis genes (GL1-4, WSL4, OsCER7, LACS2, LACS7, ROC4 and BDG) and four auxin biosynthesis genes (YUC2, YUC3, YUC5 and YUC6) was up-regulated in the Oschr4-5 mutant. Chromatin immunoprecipitation assays revealed that the transcriptionally active histone modification H3K4me3 was increased, whereas the repressive H3K27me3 was reduced in the upregulated genes in the Oschr4-5 mutant. Therefore, OsCHR4 regulates leaf morphogenesis and cuticle wax formation by epigenetic modulation of auxin and wax biosynthetic genes expression.
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Yuan, Chih-Chi, Xinyang Zhao, Laurence Florens, Selene K. Swanson, Michael P. Washburn, and Nouria Hernandez. "CHD8 Associates with Human Staf and Contributes to Efficient U6 RNA Polymerase III Transcription." Molecular and Cellular Biology 27, no. 24 (October 15, 2007): 8729–38. http://dx.doi.org/10.1128/mcb.00846-07.

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ABSTRACT Chromatin remodeling and histone modification are essential for eukaryotic transcription regulation, but little is known about chromatin-modifying activities acting on RNA polymerase III (Pol III)-transcribed genes. The human U6 small nuclear RNA promoter, located 5′ of the transcription start site, consists of a core region directing basal transcription and an activating region that recruits the transcription factors Oct-1 and Staf (ZNF143). Oct-1 activates transcription in part by helping recruit core binding factors, but nothing is known about the mechanisms of transcription activation by Staf. We show that Staf activates U6 transcription from a preassembled chromatin template in vitro and associates with several proteins linked to chromatin modification, among them chromodomain-helicase-DNA binding protein 8 (CHD8). CHD8 binds to histone H3 di- and trimethylated on lysine 4. It resides on the human U6 promoter as well as the mRNA IRF3 promoter in vivo and contributes to efficient transcription from both these promoters. Thus, Pol III transcription from type 3 promoters uses some of the same factors used for chromatin remodeling at Pol II promoters.
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Heshmati, Yaser, Gözde Turköz, Aditya Harisankar, Sten Linnarsson, Marios Dimitriou, Indranil Sinha, Sören Lehmann, Hong Qian, and Julian Walfridsson. "Identification of CHD4 As a Potential Therapeutic Target of Acute Myeloid Leukemia." Blood 128, no. 22 (December 2, 2016): 1648. http://dx.doi.org/10.1182/blood.v128.22.1648.1648.

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Abstract Acute myeloid leukemia (AML) is characterized by impaired myeloid differentiation of hematopoietic progenitors, causing uncontrolled proliferation and accumulation of immature myeloid cells in the bone marrow. Rearrangements of the mixed lineage leukemia (MLL) gene are common aberrations in acute leukemia and occur in over 70% in childhood leukemia and 5-10% in leukemia of adults. MLL rearrangements encode a fusion oncogenic H3K4 methytransferase protein, which is sufficient to transform hematopoietic cells and give rise to an aggressive subtype of AML. Leukemia where the MLL fusion oncogene is expressed is characterized by dismal prognosis and 30-60% of 5-years overall survival rate. The current standard treatment for AML is chemotherapy and in certain cases bone marrow transplantation. However, chemotherapy causes severe side effects on normal cells and an increased risk of relapse. Consequently, discovery of novel drug targets with better efficacy and low toxicity are needed to improve treatment of AML. In this study, we aimed to identify genes that are required for growth of AML cells and that encode proteins that potentially could be used as therapeutic targets. To do this, we performed high-throughput RNAi screening covering all annotated human genes and the homologous genes in mice, using barcoded lentiviral-based shRNA vectors. Stable loss-of-function screening was done in three AML cell lines (two human and one murine AML cell lines) as well as in a non-transformed hematopoietic control cell line. The candidate genes were selected based on that shRNA-mediated knockdown caused at least a 5-fold growth inhibition of leukemic cells and that the individual candidates were targeted by multiple shRNAs. The chromodomain Helicase DNA binding protein 4 (CHD4), a chromatin remodeler ATPase, displayed the most significant effect in reduced AML cell proliferation upon inhibition among the overlapping candidate genes in all three AML cell lines. CHD4 is a main subunit of the Nucleosome Remodeling Deacetylase (NuRD) complex and has been associated with epigenetic transcriptional repression. A recent study has shown that inhibition of CHD4 sensitized AML cells to genotoxic drugs by chromatin relaxation, which increases rate of double-stranded break (DSB) in leukemic cells. To verify whether CHD4 is exclusively essential for AML with MLL rearrangements, we inhibited CHD4 expression with two independent shRNAs in various AML cell lines with and without MLL translocations. In vitro monitoring of growth and viability indicated that knockdown of CHD4 efficiently suppressed growth in all tested cell lines, suggesting that CHD4 is required in general for growth of leukemic cells. To test the effect of CHD4 inhibition in normal hematopoiesis, we pursued knockdown of CHD4 and monitored effects in hematopoiesis using colony formation assays of human CD34+ cells. The results demonstrated that CHD4 knockdown had minor effects in colony formation as well as growth and survival of normal hematopoietic cells. Furthermore, to explore whether inhibition of CHD4 can prevent AML tumor growth and disease progression in vivo, we have generated a mouse model for AML. By transplanting AML cells transduced with shRNA against CHD4 into recipient mice, we showed that shRNA-mediated targeting of CHD4 not only significantly prolonged survival of AML transplanted mice but also in some cases completely rescued some mice from development of the disease. Collectively, these data suggested that CHD4 is required for AML maintenance in vivo. Next, to determine whether suppression of CHD4 can inhibit cell growth of different subpopulations and subtypes of AML, we performed loss of function studies of CHD4 on patient-derived AML cells ex vivo. Loss of CHD4 expression significantly decreased the frequency of leukemic initiating cells in different subtypes AML patient samples. In further in vivo studies using a xeno-tranplantation model for AML, we demonstrated that shRNA-mediated inhibition of CHD4 significantly reduced the frequency of leukemic cells in the marrow 6 weeks after transplantation. Taken together our results demonstrated the critical and selective role of CHD4 in propagation of patient-derived AML cells as well as in disease progression in mouse models for AML. We believe that CHD4 represents a novel potential therapeutic target that can be used to battle AML. Disclosures No relevant conflicts of interest to declare.
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Silva, Ana P. G., Daniel P. Ryan, Yaron Galanty, Jason K. K. Low, Marylene Vandevenne, Stephen P. Jackson, and Joel P. Mackay. "The N-terminal Region of Chromodomain Helicase DNA-binding Protein 4 (CHD4) Is Essential for Activity and Contains a High Mobility Group (HMG) Box-like-domain That Can Bind Poly(ADP-ribose)." Journal of Biological Chemistry 291, no. 2 (November 12, 2015): 924–38. http://dx.doi.org/10.1074/jbc.m115.683227.

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Schulten, Hans-Juergen, and Sherin Bakhashab. "Meta-Analysis of Microarray Expression Studies on Metformin in Cancer Cell Lines." International Journal of Molecular Sciences 20, no. 13 (June 28, 2019): 3173. http://dx.doi.org/10.3390/ijms20133173.

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Several studies have demonstrated that metformin (MTF) acts with variable efficiency as an anticancer agent. The pleiotropic anticancer effects of MTF on cancer cells have not been fully explored yet. By interrogating the Gene Expression Omnibus (GEO) for microarray expression data, we identified eight eligible submissions, representing five different studies, that employed various conditions including different cell lines, MTF concentrations, treatment durations, and cellular components. A compilation of the data sets of 13 different conditions contained 443 repeatedly up- and 387 repeatedly down-regulated genes; the majority of these 830 differentially expressed genes (DEGs) were associated with higher MTF concentrations and longer MTF treatment. The most frequently upregulated genes include DNA damage inducible transcript 4 (DDIT4), chromodomain helicase DNA binding protein 2 (CHD2), endoplasmic reticulum to nucleus signaling 1 (ERN1), and growth differentiation factor 15 (GDF15). The most commonly downregulated genes include arrestin domain containing 4 (ARRDC4), and thioredoxin interacting protein (TXNIP). The most significantly (p-value < 0.05, Fisher’s exact test) overrepresented protein class was entitled, nucleic acid binding. Cholesterol biosynthesis and other metabolic pathways were specifically affected by downregulated pathway molecules. In addition, cell cycle pathways were significantly related to the data set. Generated networks were significantly related to, e.g., carbohydrate and lipid metabolism, cancer, cell cycle, and DNA replication, recombination, and repair. A second compilation comprised genes that were at least under one condition up- and in at least another condition down-regulated. Herein, the most frequently deregulated genes include nuclear paraspeckle assembly transcript 1 (NEAT1) and insulin induced gene 1 (INSIG1). The most significantly overrepresented protein classes in this compilation were entitled, nucleic acid binding, ubiquitin-protein ligase, and mRNA processing factor. In conclusion, this study provides a comprehensive list of deregulated genes and biofunctions related to in vitro MTF application and individual responses to different conditions. Biofunctions affected by MTF include, e.g., cholesterol synthesis and other metabolic pathways, cell cycle, and DNA replication, recombination, and repair. These findings can assist in defining the conditions in which MTF exerts additive or synergistic effects in cancer treatment.
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Nio, Kouki, Taro Yamashita, and Shuichi Kaneko. "Chromodomain-helicase-DNA-binding protein 4: a novel therapeutic target in liver cancer stem cells." Chinese Clinical Oncology 6, no. 1 (February 2017): 12. http://dx.doi.org/10.21037/cco.2016.07.01.

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Wong, Sze Chuen Cesar, Moon Tong Cheung, Lewis Lai Yin Luk, Vivian Ha Man Lee, Pak Tat Chan, Hin Fung Andy Tsang, Evelyn Yin Kwan Wong, Vivian Weiwen Xue, Amanda Kit Ching Chan, and John Kwok Cheung Chan. "Prognostic significance of Cytokeratin 20-positive lymph node vascular endothelial growth factor A mRNA and chromodomain helicase DNA binding protein 4 in pN0 colorectal cancer patients." Oncotarget 9, no. 6 (December 19, 2017): 6737–51. http://dx.doi.org/10.18632/oncotarget.23424.

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Bagi, Zoltán, Katalin Balog, Bianka Tóth, Milán Fehér, Péter Bársony, Edina Baranyai, Sándor Harangi, et al. "Genes and elements involved in the regulation of the nervous system and growth affect the development of spinal deformity in Cyprinus carpio." PLOS ONE 17, no. 4 (April 8, 2022): e0266447. http://dx.doi.org/10.1371/journal.pone.0266447.

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Spinal deformity is a serious economic and animal welfare problem in intensive fish farming systems, which will be a significant unsolved problem for the fish sector. The aim of this study was to determine the relative expression of genes (Akt1 substrate 1, Calreticulin, Collagen type I alpha 2 chain, Corticotropin-releasing hormone, Chromodomain-Helicase DNA-binding, Growth hormone, Insulin like growth factor 1, Myostatin, Sine oculis-related homeobox 3, Toll-like receptor 2) in different tissues associated with spinal deformity and to determine the macroelement (calcium, magnesium, phosphorus, potassium, sodium, sulfur) and microelement (barium, copper, iron, manganese, strontium, zinc) content of spine in healthy and deformed common carps (Cyprinus carpio) in Hungary. The mRNA levels of the genes were measured in 7 different tissues (abdominal fat, blood, brain, dorsal muscle, genitals, heart, liver) by qRT-PCR. Correlations between gene expression and element content were analyzed by using linear regression and Spearman rank correlation. In a total of 15 cases, we found a statistically significant connection between gene expression in a tissue and the macro- or microelement content of the spine. In these contexts, the genes Akt1 substrate 1 (3), Collagen type I alpha 2 chain (2), Corticotropin-releasing hormone (4), Insulin-like growth factor 1 (4), and Myostatin (2), the tissue’s blood (3), brain (6), heart (5), and liver (1), the macroelements sodium (4), magnesium (4), phosphorus (1) and sulfur (2) as well as the microelement iron (4) were involved. We also found statistically significant mRNA level differences between healthy and deformed common carps in tissues that were not directly affected by the deformation. Based on our results, genes regulating the nervous system and growth, elements, and tissues are the most associated components in the phenomenon of spinal deformity. With our study, we wish to give direction to and momentum for the exploration of these complex processes.
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Novillo, Apolonia, Ana Fernández-Santander, Maria Gaibar, Miguel Galán, Alicia Romero-Lorca, Fadoua El Abdellaoui-Soussi, and Pablo Gómez-del Arco. "Role of Chromodomain-Helicase-DNA-Binding Protein 4 (CHD4) in Breast Cancer." Frontiers in Oncology 11 (April 26, 2021). http://dx.doi.org/10.3389/fonc.2021.633233.

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Chromodomain-helicase-DNA-binding protein 4 (CHD4) is an epigenetic regulator identified as an oncogenic element that may provide a novel therapeutic target for the treatment of breast cancer (BC). CHD4—the core component of the nucleosome remodeling and deacetylase (NuRD) complex—may be mutated in patients with this disease. However, information on CHD4 mutants that might allow their use as biomarkers of therapeutic success and prognosis is lacking. The present work examines mutations in CHD4 reported in patients with breast cancer and included in public databases and attempts to identify their roles in its development. The databases revealed 81 point mutations across different types of breast cancer (19 of which also appeared in endometrial, intestinal, nervous system, kidney, and lymphoid organ cancers). 71.6% of the detected mutations were missense mutations, 13.6% were silent, and 6.2% nonsense. Over 50% affected conserved residues of the ATPase motor (ATPase and helicase domains), and domains of unknown function in the C-terminal region. Thirty one mutations were classified in the databases as either ‘deleterious’, ‘probably/possibly damaging’ or as ‘high/medium pathogenic’; another five nonsense and one splice-site variant were predicted to produce potentially harmful truncated proteins. Eight of the 81 mutations were categorized as putative driver mutations and have been found in other cancer types. Some mutations seem to influence ATPase and DNA translocation activities (R1162W), while others may alter protein stability (R877Q/H, R975H) or disrupt DNA binding and protein activity (R572*, X34_splice) suggesting CHD4 function may be affected. In vivo tumorigenecity studies in endometrial cancer have revealed R975H and R1162W as mutations that lead to CHD4 loss-of-function. Our study provides insight into the molecular mechanism whereby CHD4, and some of its mutants could play a role in breast cancer and suggest important implications for the biological comprehension and prognosis of breast cancer, identifying CHD4 as a novel therapeutic target for BC patients.
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Helness, Anne, Jennifer Fraszczak, Charles Joly-Beauparlant, Halil Bagci, Christian Trahan, Kaifee Arman, Peiman Shooshtarizadeh, et al. "GFI1 tethers the NuRD complex to open and transcriptionally active chromatin in myeloid progenitors." Communications Biology 4, no. 1 (December 2021). http://dx.doi.org/10.1038/s42003-021-02889-2.

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AbstractGrowth factor indepdendent 1 (GFI1) is a SNAG-domain, DNA binding transcriptional repressor which controls myeloid differentiation through molecular mechanisms and co-factors that still remain to be clearly identified. Here we show that GFI1 associates with the chromodomain helicase DNA binding protein 4 (CHD4) and other components of the Nucleosome remodeling and deacetylase (NuRD) complex. In granulo-monocytic precursors, GFI1, CHD4 or GFI1/CHD4 complexes occupy sites enriched for histone marks associated with active transcription suggesting that GFI1 recruits the NuRD complex to target genes regulated by active or bivalent promoters and enhancers. GFI1 and GFI1/CHD4 complexes occupy promoters that are either enriched for IRF1 or SPI1 consensus binding sites, respectively. During neutrophil differentiation, chromatin closure and depletion of H3K4me2 occurs at different degrees depending on whether GFI1, CHD4 or both are present, indicating that GFI1 is more efficient in depleting of H3K4me2 and -me1 marks when associated with CHD4. Our data suggest that GFI1/CHD4 complexes regulate histone modifications differentially to enable regulation of target genes affecting immune response, nucleosome organization or cellular metabolic processes and that both the target gene specificity and the activity of GFI1 during myeloid differentiation depends on the presence of chromatin remodeling complexes.
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Li, Pengyu, Jielin Tang, Zhixin Yu, Cheng Jin, Zhipeng Wang, Mengzhen Li, Dingfeng Zou, et al. "CHD4 acts as a critical regulator in the survival of spermatogonial stem cells in mice." Biology of Reproduction, August 18, 2022. http://dx.doi.org/10.1093/biolre/ioac162.

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Abstract Spermatogenesis is sustained by homeostatic balance between the self-renewal and differentiation of spermatogonial stem cells (SSCs), which is dependent on the strict regulation of transcription factor and chromatin modulator gene expression. Chromodomain helicase DNA-binding protein 4 (CHD4) is highly expressed in SSCs but roles in mouse spermatogenesis are not fully understood. Here, we report that the germ-cell-specific deletion of Chd4 resulted in complete infertility in male mice, with rapid loss of SSCs and excessive germ cell apoptosis. Chd4-knockdown in cultured SSCs also promoted the expression of apoptosis-related genes and thereby activated the tumor necrosis factor signaling pathway. Mechanistically, CHD4 occupies the genomic regulatory region of key apoptosis-related genes including Jun and Nfkb1. Together, our findings reveal the determinant role of CHD4 in SSCs survival in vivo, which will offer insight into the pathogenesis of male sterility and potential novel therapeutic targets.
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Geyer, Fabian, Maximilian Geyer, Ute Reuning, Sarah Klapproth, Klaus-Dietrich Wolff, and Markus Nieberler. "CHD4 acts as a prognostic factor and drives radioresistance in HPV negative HNSCC." Scientific Reports 14, no. 1 (April 9, 2024). http://dx.doi.org/10.1038/s41598-024-58958-z.

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AbstractDespite great efforts in improving existing therapies, the outcome of patients with advanced radioresistant HPV-negative head and neck squamous cell carcinoma (HNSCC) remains poor. The chromatin remodeler Chromodomain helicase DNA binding protein 4 (CHD4) is involved in different DNA-repair mechanisms, but the role and potential in HNSCC has not been explored yet. In the present study, we evaluated the prognostic significance of CHD4 expression using in silico analysis of the pan-cancer dataset. Furthermore, we established a monoclonal HNSCC CHD4 knockdown cell clone utilizing the CRISPR/Cas9 system. Effects of lower CHD4 expression on radiosensitivity after increasing doses of ionizing radiation were characterized using clonogenic assays and cell numbers. The in silico analysis revealed that high CHD4 expression is associated with significant poorer overall survival of HPV-negative HNSCC patients. Additionally, the knockdown of CHD4 significantly increased the radiosensitivity of HNSCC cells. Therefore, CHD4 might be involved in promoting radioresistance in hard-to-treat HPV-negative HNSCC entities. We conclude that CHD4 could serve as a prognostic factor in HPV-negative HNSCC tumors and is a potential target protein overcoming radioresistance in HNSCC. Our results and the newly established cell clone laid the foundation to further characterize the underlying mechanisms and ultimately use CHD4 in HNSCC therapies.
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Shi, Wei, Angel P. Scialdone, James I. Emerson, Liu Mei, Lauren K. Wasson, Haley A. Davies, Christine E. Seidman, Jonathan G. Seidman, Jeanette G. Cook, and Frank L. Conlon. "Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1." Circulation Research, May 31, 2023. http://dx.doi.org/10.1161/circresaha.122.322223.

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Background: Left ventricular noncompaction (LVNC) is a prevalent cardiomyopathy associated with excessive trabeculation and thin compact myocardium. Patients with LVNC are vulnerable to cardiac dysfunction and at high risk of sudden death. Although sporadic and inherited mutations in cardiac genes are implicated in LVNC, understanding of the mechanisms responsible for human LVNC is limited. Methods: We screened the complete exome sequence database of the Pediatrics Cardiac Genomics Consortium and identified a cohort with a de novo CHD4 (chromodomain helicase DNA-binding protein 4) proband, CHD4 M202I , with congenital heart defects. We engineered a humanized mouse model of CHD4 M202I (mouse CHD4 M195I ). Histological analysis, immunohistochemistry, flow cytometry, transmission electron microscopy, and echocardiography were used to analyze cardiac anatomy and function. Ex vivo culture, immunopurification coupled with mass spectrometry, transcriptional profiling, and chromatin immunoprecipitation were performed to deduce the mechanism of CHD4 M195I -mediated ventricular wall defects. Results: CHD4 M195I/M195I mice developed biventricular hypertrabeculation and noncompaction and died at birth. Proliferation of cardiomyocytes was significantly increased in CHD4 M195I hearts, and the excessive trabeculation was associated with accumulation of ECM (extracellular matrix) proteins and a reduction of ADAMTS1 (ADAM metallopeptidase with thrombospondin type 1 motif 1), an ECM protease. We rescued the hyperproliferation and hypertrabeculation defects in CHD4 M195I hearts by administration of ADAMTS1. Mechanistically, the CHD4 M195I protein showed augmented affinity to endocardial BRG1 (SWI/SNF–related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4). This enhanced affinity resulted in the failure of derepression of Adamts1 transcription such that ADAMTS1-mediated trabeculation termination was impaired. Conclusions: Our study reveals how a single mutation in the chromatin remodeler CHD4, in mice or humans, modulates ventricular chamber maturation and that cardiac defects associated with the missense mutation CHD4 M195I can be attenuated by the administration of ADAMTS1.
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Wu, Meng-Ling, Kate Wheeler, Robert Silasi, Florea Lupu, and Courtney T. Griffin. "Endothelial Chromatin-Remodeling Enzymes Regulate the Production of Critical ECM Components During Murine Lung Development." Arteriosclerosis, Thrombosis, and Vascular Biology, June 13, 2024. http://dx.doi.org/10.1161/atvbaha.124.320881.

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BACKGROUND: The chromatin-remodeling enzymes BRG1 (brahma-related gene 1) and CHD4 (chromodomain helicase DNA-binding protein 4) independently regulate the transcription of genes critical for vascular development, but their coordinated impact on vessels in late-stage embryos has not been explored. METHODS: In this study, we genetically deleted endothelial Brg1 and Chd4 in mixed background mice ( Brg1 fl/fl ;Chd4 fl/fl ;VE-Cadherin-Cre + ), and littermates that were negative for Cre recombinase were used as controls. Tissues were analyzed by immunostaining, immunoblot, and flow cytometry. Quantitative reverse transcription polymerase chain reaction was used to determine gene expression, and chromatin immunoprecipitation revealed gene targets of BRG1 and CHD4 in cultured endothelial cells. RESULTS: We found Brg1/Chd4 double mutants grew normally but died soon after birth with small and compact lungs. Despite having normal cellular composition, distal air sacs of the mutant lungs displayed diminished ECM (extracellular matrix) components and TGFβ (transforming growth factor-β) signaling, which typically promotes ECM synthesis. Transcripts for collagen- and elastin-related genes and the TGFβ ligand Tgfb1 were decreased in mutant lung endothelial cells, but genetic deletion of endothelial Tgfb1 failed to recapitulate the small lungs and ECM defects seen in Brg1/Chd4 mutants. We instead found several ECM genes to be direct targets of BRG1 and CHD4 in cultured endothelial cells. CONCLUSIONS: Collectively, our data highlight essential roles for endothelial chromatin-remodeling enzymes in promoting ECM deposition in the distal lung tissue during the saccular stage of embryonic lung development.
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Schilders, Kim A. A., Gabriëla G. Edel, Evelien Eenjes, Bianca Oresta, Judith Birkhoff, Anne Boerema-de Munck, Marjon Buscop-van Kempen, et al. "Identification of SOX2 Interacting Proteins in the Developing Mouse Lung With Potential Implications for Congenital Diaphragmatic Hernia." Frontiers in Pediatrics 10 (May 9, 2022). http://dx.doi.org/10.3389/fped.2022.881287.

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Congenital diaphragmatic hernia is a structural birth defect of the diaphragm, with lung hypoplasia and persistent pulmonary hypertension. Aside from vascular defects, the lungs show a disturbed balance of differentiated airway epithelial cells. The Sry related HMG box protein SOX2 is an important transcription factor for proper differentiation of the lung epithelium. The transcriptional activity of SOX2 depends on interaction with other proteins and the identification of SOX2-associating factors may reveal important complexes involved in the disturbed differentiation in CDH. To identify SOX2-associating proteins, we purified SOX2 complexes from embryonic mouse lungs at 18.5 days of gestation. Mass spectrometry analysis of SOX2-associated proteins identified several potential candidates, among which were the Chromodomain Helicase DNA binding protein 4 (CHD4), Cut-Like Homeobox1 (CUX1), and the Forkhead box proteins FOXP2 and FOXP4. We analyzed the expression patterns of FOXP2, FOXP4, CHD4, and CUX1 in lung during development and showed co-localization with SOX2. Co-immunoprecipitations validated the interactions of these four transcription factors with SOX2, and large-scale chromatin immunoprecipitation (ChIP) data indicated that SOX2 and CHD4 bound to unique sites in the genome, but also co-occupied identical regions, suggesting that these complexes could be involved in co-regulation of genes involved in the respiratory system.
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Pinal-Fernandez, Iago, Jose Cesar Milisenda, Katherine Pak, Sandra Muñoz-Braceras, Maria Casal-Dominguez, Jiram Torres-Ruiz, Stefania Dell'Orso, et al. "Transcriptional derepression of CHD4/NuRD-regulated genes in the muscle of patients with dermatomyositis and anti-Mi2 autoantibodies." Annals of the Rheumatic Diseases, May 2, 2023, ard—2023–223873. http://dx.doi.org/10.1136/ard-2023-223873.

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ObjectivesMyositis is a heterogeneous family of diseases including dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), antisynthetase syndrome (AS) and inclusion body myositis (IBM). Myositis-specific autoantibodies define different subtypes of myositis. For example, patients with anti-Mi2 autoantibodies targeting the chromodomain helicase DNA-binding protein 4 (CHD4)/NuRD complex (a transcriptional repressor) have more severe muscle disease than other DM patients. This study aimed to define the transcriptional profile of muscle biopsies from anti-Mi2-positive DM patients.MethodsRNA sequencing was performed on muscle biopsies (n=171) from patients with anti-Mi2-positive DM (n=18), DM without anti-Mi2 autoantibodies (n=32), AS (n=18), IMNM (n=54) and IBM (n=16) as well as 33 normal muscle biopsies. Genes specifically upregulated in anti-Mi2-positive DM were identified. Muscle biopsies were stained for human immunoglobulin and protein products corresponding to genes specifically upregulated in anti-Mi2-positive muscle biopsies.ResultsA set of 135 genes, includingSCRT1andMADCAM1, was specifically overexpressed in anti-Mi2-positive DM muscle. This set was enriched for CHD4/NuRD-regulated genes and included genes that are not otherwise expressed in skeletal muscle. The expression levels of these genes correlated with anti-Mi2 autoantibody titres, markers of disease activity and with the other members of the gene set. In anti-Mi2-positive muscle biopsies, immunoglobulin was localised to the myonuclei, MAdCAM-1 protein was present in the cytoplasm of perifascicular fibres, and SCRT1 protein was localised to myofibre nuclei.ConclusionsBased on these findings, we hypothesise that anti-Mi2 autoantibodies could exert a pathogenic effect by entering damaged myofibres, inhibiting the CHD4/NuRD complex, and subsequently derepressing the unique set of genes defined in this study.
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Xiao, Guodong, Weiping Lu, Jing Yuan, Zuyue Liu, Peili Wang, and Huijie Fan. "Fbxw7 suppresses carcinogenesis and stemness in triple-negative breast cancer through CHD4 degradation and Wnt/β-catenin pathway inhibition." Journal of Translational Medicine 22, no. 1 (January 24, 2024). http://dx.doi.org/10.1186/s12967-024-04897-2.

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Abstract Background Cancer stem cells (CSCs) are a small population of cells in tumor tissues that can drive tumor initiation and promote tumor progression. A small number of previous studies indirectly mentioned the role of F-box and WD repeat domain-containing 7 (FBXW7) as a tumor suppressor in Triple-negative breast cancer (TNBC). However, few studies have focused on the function of FBXW7 in cancer stemness in TNBC and the related mechanism. Methods We detected FBXW7 by immunohistochemistry (IHC) in 80 TNBC patients. FBXW7 knockdown and overexpression in MD-MBA-231 and HCC1937 cell models were constructed. The effect of FBXW7 on malignant phenotype and stemness was assessed by colony assays, flow cytometry, transwell assays, western blot, and sphere formation assays. Immunoprecipitation-Mass Spectrometry (IP-MS) and ubiquitination experiments were used to find and verify potential downstream substrate proteins of FBXW7. Animal experiments were constructed to examine the effect of FBXW7 on tumorigenic potential and cancer stemness of TNBC cells in vivo. Results The results showed that FBXW7 was expressed at low levels in TNBC tissues and positively correlated with prognosis of TNBC patients. In vitro, FBXW7 significantly inhibited colony formation, cell cycle progression, cell migration, EMT process, cancer stemness and promotes apoptosis. Further experiments confirmed that chromodomain-helicase-DNA-binding protein 4 (CHD4) is a novel downstream target of FBXW7 and is downregulated by FBXW7 via proteasomal degradation. Moreover, CHD4 could promote the nuclear translocation of β-catenin and reverse the inhibitory effect of FBXW7 on β-catenin, and ultimately activate the Wnt/β-catenin pathway. Rescue experiments confirmed that the FBXW7-CHD4-Wnt/β-catenin axis was involved in regulating the maintenance of CSC in TNBC cells. In animal experiments, FBXW7 reduced CSC marker expression and suppressed TNBC cell tumorigenesis in vivo. Conclusions Taken together, these results highlight that FBXW7 degrades CHD4 protein through ubiquitination, thereby blocking the activation of the Wnt/β-catenin pathway to inhibit the stemness of TNBC cells. Thus, targeting FBXW7 may be a promising strategy for therapeutic intervention against TNBC.
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Yao, Hui, Douglas F. Hannum, Yiwen Zhai, Sophie F. Hill, Ricardo D. ’Oliveira Albanus, Wenjia Lou, Jennifer M. Skidmore, et al. "CHD7 promotes neural progenitor differentiation in embryonic stem cells via altered chromatin accessibility and nascent gene expression." Scientific Reports 10, no. 1 (October 15, 2020). http://dx.doi.org/10.1038/s41598-020-74537-4.

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Abstract CHARGE syndrome, a rare multiple congenital anomaly condition, is caused by haploinsufficiency of the chromatin remodeling protein gene CHD7 (Chromodomain helicase DNA binding protein 7). Brain abnormalities and intellectual disability are commonly observed in individuals with CHARGE, and neuronal differentiation is reduced in CHARGE patient-derived iPSCs and conditional knockout mouse brains. However, the mechanisms of CHD7 function in nervous system development are not well understood. In this study, we asked whether CHD7 promotes gene transcription in neural progenitor cells via changes in chromatin accessibility. We used Chd7 null embryonic stem cells (ESCs) derived from Chd7 mutant mouse blastocysts as a tool to investigate roles of CHD7 in neuronal and glial differentiation. Loss of Chd7 significantly reduced neuronal and glial differentiation. Sholl analysis showed that loss of Chd7 impaired neuronal complexity and neurite length in differentiated neurons. Genome-wide studies demonstrated that loss of Chd7 leads to modified chromatin accessibility (ATAC-seq) and differential nascent expression (Bru-Seq) of neural-specific genes. These results suggest that CHD7 acts preferentially to alter chromatin accessibility of key genes during the transition of NPCs to neurons to promote differentiation. Our results form a basis for understanding the cell stage-specific roles for CHD7-mediated chromatin remodeling during cell lineage acquisition.
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Zhang, Zhen, Flávia C. Costa, Ee Phie Tan, Nathan Bushue, Catherine E. Costello, Mark E. McComb, Stephen A. Whelan, Kenneth R. Peterson, and Chad Slawson. "O‐GlcNAc Transferase and O‐GlcNAcase Interact with Mi2β at the Aγ‐Globin Promoter." FASEB Journal 30, S1 (April 2016). http://dx.doi.org/10.1096/fasebj.30.1_supplement.803.3.

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Sickle Cell Disease (SCD), caused by a point mutation in the adult β‐globin gene, leads to chronic damage to multiple organs and stroke, as well as cardiovascular abnormalities and dysfunction. However, SCD patients are phenotypically normal if they carry compensatory mutations that result in continued expression of fetal γ‐globin. Thus, a logical clinical goal for treatment of SCD is to up‐regulate fetal γ‐globin synthesis. One mode of γ‐globin silencing occurs at the GATA binding sites located at −566 or −567 relative to the Aγ‐globin or Gγ‐globin transcription start site, respectively, and is mediated through the DNA binding moiety GATA‐1 (GATA Binding Protein 1) and its recruitment of co‐repressor partners, FOG‐1 (Friend of GATA‐1) and Mi2β (CHD4, Chromodomain Helicase DNA Binding Protein 4). Post‐translational modification of transcription factors can regulate their activity. One such modification is O‐GlcNAcylation, which is the attachment of a single N‐acetyl‐glucosamine moiety to serine or threonine residues on nuclear, cytoplasmic and mitochondrial proteins. O‐GlcNAc is added to proteins by O‐GlcNAc transferase (OGT) and removed by O‐GlcNAcase (OGA). Here, using ChIP (Chromatin Immunoprecipitation) assays, we demonstrate that both OGT and OGA interact with the Aγ‐globin promoter when Aγ‐globin is repressed in wild‐type murine CID (Chemical Inducer of Dimerization)‐dependent human β‐YAC (β‐globin locus yeast artificial chromosome) bone marrow cells (BMCs). In addition, Mi2β and OGT are recruited to the −566 Aγ‐globin GATA silencer site in mouse embryonic day E18 fetal liver when Aγ‐globin is repressed. Furthermore, we demonstrate that OGT and OGA interact with Mi2β and FOG‐1, and Mi2β and FOG‐1 are O‐GlcNAcylated using co‐immunoprecipitation experiments. In order to confirm Mi2β O‐GlcNAcylation, we mapped one O‐GlcNAc site at S85 by mass spectrometry. Our data suggested that OGT and OGA can regulate GATA‐1/FOG‐1/Mi2β repressor complex activity at the Aγ‐globin promoter.Support or Funding InformationResearch reported in this publication was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences (NIGMS) of the National Institutes for Health under grant P20 GM12345, National Institute of Diabetes and Digestive and Kidney Diseases R01 DK100595 to C. Slawson and K. Peterson, and by National Heart, Lung, and Blood Institute contract HHSN268201000031C and NIGMS grant P41 GM104603 to C. E. Costello.
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Xu, Weiwei, Weibin Zhou, Haiyang Lin, Dan Ye, Guoping Chen, Fengqin Dong, and Jianguo Shen. "A novel heterozygous mutation of CHD7 gene in a Chinese patient with Kallmann syndrome: a case report." BMC Endocrine Disorders 21, no. 1 (September 25, 2021). http://dx.doi.org/10.1186/s12902-021-00836-0.

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Abstract Background Variants of chromodomain helicase DNA binding protein 7 (CHD7) gene are commonly associated with Kallmann syndrome (KS) and account for 5–6% of idiopathic hypogonadotropic hypogonadism (IHH) cases. Here we report a novel mutation of CHD7 gene in a patient with KS, which may contribute to the better understanding of KS. Case presentation A 29-year-old male patient with KS and a chief complaint of delayed puberty for 13 years (Tanner B Stage< 4) was admitted to the Department of Endocrinology of the First Affiliated Hospital of Zhejiang University (Hangzhou, China) in September 2019. Dual-energy X-ray absorptiometry (DEXA) showed low bone density in both lumbar spine (L1 ~ L5 mean Z-score − 3.0) and femoral neck (Z-score − 2.7). Dynamic contrast-enhanced magnetic resonance imaging (MRI) of pituitary and contrast-enhanced computed tomography (CT) showed no abnormal findings. Ophthalmological evaluation showed that his both eyes showed exotropia, and no sight loss was noted. Heterozygous c.1619G > T mutation of TCD7 gene (p.G4856V) was detected, whereas none of his family members had this mutation. Human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) were injected for three times/week to treat idiopathic hypogonadotropic hypogonadism (IHH). After several months of therapy, the patient’s health condition improved. His testicles became larger, and his secondary sexual characteristics improved after treatment. Conclusion Exploration of the novel splice-site mutation of CHD7 may further our current understanding of KS.
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Laureano, Alejandra, Jihyun Kim, Edward Martinez, and Kelvin Y. Kwan. "Chromodomain Helicase DNA Binding Protein 4 in Cell Fate Decisions." Hearing Research, May 2023, 108813. http://dx.doi.org/10.1016/j.heares.2023.108813.

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Muhammad, Tahir, Stephen F. Pastore, Katrina Good, Juan Ausió, and John B. Vincent. "Chromatin gatekeeper and modifier CHD proteins in development, and in autism and other neurological disorders." Psychiatric Genetics, October 16, 2023. http://dx.doi.org/10.1097/ypg.0000000000000353.

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Chromatin, a protein–DNA complex, is a dynamic structure that stores genetic information within the nucleus and adapts to molecular/cellular changes in its structure, providing conditional access to the genetic machinery. ATP-dependent chromatin modifiers regulate access of transcription factors and RNA polymerases to DNA by either “opening” or “closing” the structure of chromatin, and its aberrant regulation leads to a variety of neurodevelopmental disorders. The chromodomain helicase DNA-binding (CHD) proteins are ATP-dependent chromatin modifiers involved in the organization of chromatin structure, act as gatekeepers of genomic access, and deposit histone variants required for gene regulation. In this review, we first discuss the structural and functional domains of the CHD proteins, and their binding sites, and phosphorylation, acetylation, and methylation sites. The conservation of important amino acids in SWItch/sucrose non-fermenting (SWI/SNF) domains, and their protein and mRNA tissue expression profiles are discussed. Next, we convey the important binding partners of CHD proteins, their protein complexes and activities, and their involvements in epigenetic regulation. We also show the ChIP-seq binding dynamics for CHD1, CHD2, CHD4, and CHD7 proteins at promoter regions of histone genes, as well as several genes that are critical for neurodevelopment. The role of CHD proteins in development is also discussed. Finally, this review provides information about CHD protein mutations reported in autism and neurodevelopmental disorders, and their pathogenicity. Overall, this review provides information on the progress of research into CHD proteins, their structural and functional domains, epigenetics, and their role in stem cell, development, and neurological disorders.
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Coassolo, Sébastien, Guillaume Davidson, Luc Negroni, Giovanni Gambi, Sylvain Daujat, Christophe Romier, and Irwin Davidson. "Citrullination of pyruvate kinase M2 by PADI1 and PADI3 regulates glycolysis and cancer cell proliferation." Nature Communications 12, no. 1 (March 19, 2021). http://dx.doi.org/10.1038/s41467-021-21960-4.

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AbstractChromodomain helicase DNA binding protein 4 (CHD4) is an ATPase subunit of the Nucleosome Remodelling and Deacetylation (NuRD) complex that regulates gene expression. CHD4 is essential for growth of multiple patient derived melanoma xenografts and for breast cancer. Here we show that CHD4 regulates expression of PADI1 (Protein Arginine Deiminase 1) and PADI3 in multiple cancer cell types modulating citrullination of arginine residues of the allosterically-regulated glycolytic enzyme pyruvate kinase M2 (PKM2). Citrullination of PKM2 R106 reprogrammes cross-talk between PKM2 ligands lowering its sensitivity to the inhibitors Tryptophan, Alanine and Phenylalanine and promoting activation by Serine. Citrullination thus bypasses normal physiological regulation by low Serine levels to promote excessive glycolysis and reduced cell proliferation. We further show that PADI1 and PADI3 expression is up-regulated by hypoxia where PKM2 citrullination contributes to increased glycolysis. We provide insight as to how conversion of arginines to citrulline impacts key interactions within PKM2 that act in concert to reprogramme its activity as an additional mechanism regulating this important enzyme.
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D’Incal, Claudio Peter, Kirsten Esther Van Rossem, Kevin De Man, Anthony Konings, Anke Van Dijck, Ludovico Rizzuti, Alessandro Vitriolo, et al. "Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism." Clinical Epigenetics 15, no. 1 (March 21, 2023). http://dx.doi.org/10.1186/s13148-023-01450-8.

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Abstract Background Individuals affected with autism often suffer additional co-morbidities such as intellectual disability. The genes contributing to autism cluster on a relatively limited number of cellular pathways, including chromatin remodeling. However, limited information is available on how mutations in single genes can result in such pleiotropic clinical features in affected individuals. In this review, we summarize available information on one of the most frequently mutated genes in syndromic autism the Activity-Dependent Neuroprotective Protein (ADNP). Results Heterozygous and predicted loss-of-function ADNP mutations in individuals inevitably result in the clinical presentation with the Helsmoortel–Van der Aa syndrome, a frequent form of syndromic autism. ADNP, a zinc finger DNA-binding protein has a role in chromatin remodeling: The protein is associated with the pericentromeric protein HP1, the SWI/SNF core complex protein BRG1, and other members of this chromatin remodeling complex and, in murine stem cells, with the chromodomain helicase CHD4 in a ChAHP complex. ADNP has recently been shown to possess R-loop processing activity. In addition, many additional functions, for instance, in association with cytoskeletal proteins have been linked to ADNP. Conclusions We here present an integrated evaluation of all current aspects of gene function and evaluate how abnormalities in chromatin remodeling might relate to the pleiotropic clinical presentation in individual“s” with Helsmoortel–Van der Aa syndrome.
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Jiang, Dongfang, Tingting Li, Caixia Guo, Tie-Shan Tang, and Hongmei Liu. "Small molecule modulators of chromatin remodeling: from neurodevelopment to neurodegeneration." Cell & Bioscience 13, no. 1 (January 16, 2023). http://dx.doi.org/10.1186/s13578-023-00953-4.

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AbstractThe dynamic changes in chromatin conformation alter the organization and structure of the genome and further regulate gene transcription. Basically, the chromatin structure is controlled by reversible, enzyme-catalyzed covalent modifications to chromatin components and by noncovalent ATP-dependent modifications via chromatin remodeling complexes, including switch/sucrose nonfermentable (SWI/SNF), inositol-requiring 80 (INO80), imitation switch (ISWI) and chromodomain-helicase DNA-binding protein (CHD) complexes. Recent studies have shown that chromatin remodeling is essential in different stages of postnatal and adult neurogenesis. Chromatin deregulation, which leads to defects in epigenetic gene regulation and further pathological gene expression programs, often causes a wide range of pathologies. This review first gives an overview of the regulatory mechanisms of chromatin remodeling. We then focus mainly on discussing the physiological functions of chromatin remodeling, particularly histone and DNA modifications and the four classes of ATP-dependent chromatin-remodeling enzymes, in the central and peripheral nervous systems under healthy and pathological conditions, that is, in neurodegenerative disorders. Finally, we provide an update on the development of potent and selective small molecule modulators targeting various chromatin-modifying proteins commonly associated with neurodegenerative diseases and their potential clinical applications.
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Schulz, Vanessa E., Jeffrey F. Tuff, Riley H. Tough, Lara Lewis, Benjamin Chimukangara, Nigel Garrett, Quarraisha Abdool Karim, et al. "Host genetic variation at a locus near CHD1L impacts HIV sequence diversity in a South African population." Journal of Virology, September 25, 2023. http://dx.doi.org/10.1128/jvi.00954-23.

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ABSTRACT There is variability in viral load (VL) among individuals with untreated human immunodeficiency virus (HIV) infection, and this variability can be partly attributed to host genetics. HIV is known to develop escape mutations to evade host immune pressure, particularly from HLA alleles and, in some cases, counteracts the protective effect of host alleles. A recent genome-wide association study (GWAS) of HIV VL in individuals of African ancestry identified a locus on chromosome 1, near the protein-coding gene chromodomain helicase DNA-binding protein 1 like ( CHD1L ), that has a novel association with control of HIV replication. However, not all individuals carrying the protective alleles maintain low VL, and the region’s impact on viral evolution has not been investigated. To address this, we conducted a host-virus regional association analysis in 147 people living with HIV (PLWH) from South Africa with both human and viral genome data available. We observed significant associations between the CHD1L variants rs77029719 (G) ( P = 1.6 × 10 −2 ), rs7519713 (T) ( P = 2.3 × 10 −2 ), and rs59784663 (G) and 73004025 (T) ( P = 1.4 × 10 −2 ) with codon 248 of HIV reverse transcriptase (RT) and between CHD1L variant rs7519713 (T) and codon 18 ( P = 3.2 × 10 −2 ) and 147 ( P = 3.9 × 10 −2 ) of HIV gag. These associations are consistent with viral escape from CHD1L pressure. In addition, we observed significant associations between HLA B*81 ( P = 1.5 × 10 −5 ) and HLA C*18 ( P = 7.0 × 10 −4 ) with RT codon 4 and HLAB*58 with RT codon 196 ( P = 9.0 × 10 −4 ). This study reveals new evidence of host genetic variation impacting viral evolution in a population highly affected by HIV. IMPORTANCE It has been previously shown that genetic variants near CHD1L on chromosome 1 are associated with reduced HIV VL in African populations. However, the impact of these variants on viral diversity and how they restrict viral replication are unknown. We report on a regional association analysis in a South African population and show evidence of selective pressure by variants near CHD1L on HIV RT and gag. Our findings provide further insight into how genetic variability at this locus contributes to host control of HIV in a South African population.

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