Journal articles: 'Remodelled genes'

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Germain, Adeline, Jeanne-Marie Perotin, Gonzague Delepine, Myriam Polette, Gaëtan Deslée, and Valérian Dormoy. "Whole-Exome Sequencing of Bronchial Epithelial Cells Reveals a Genetic Print of Airway Remodelling in COPD." Biomedicines 10, no. 7 (July 15, 2022): 1714. http://dx.doi.org/10.3390/biomedicines10071714.

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The remodelling of the airways is a hallmark of chronic obstructive pulmonary disease, but it is highly heterogeneous and erratically distributed in the airways. To assess the genetic print of remodelling in chronic obstructive pulmonary disease (COPD), we performed a comparative whole-exome sequencing analysis on microdissected bronchial epithelia. Lung resections from four non-COPD and three COPD subjects (ex-smokers and current smokers) were formalin-fixed paraffin-embedded (FFPE). Non-remodelled and remodelled bronchial epithelia were isolated by laser microdissection. Genomic DNA was captured and sequenced. The comparative quantitative analysis identified a list of 109 genes as having variants in remodelled epithelia and 160 genes as having copy number alterations in remodelled epithelia, mainly in COPD patients. The functional analysis highlighted cilia-associated processes. Therefore, bronchial-remodelled epithelia appeared genetically more altered than non-remodelled epithelia. Characterizing the unique molecular print of airway remodelling in respiratory diseases may help uncover additional factors contributing to epithelial dysfunctions, ultimately providing additional targetable proteins to correct epithelial remodelling and improve lung function.

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Li, Mengyao, Su Mon Aye, Maizbha Uddin Ahmed, Mei-Ling Han, Chen Li, Jiangning Song, John D. Boyce, et al. "Pan-transcriptomic analysis identified common differentially expressed genes of Acinetobacter baumannii in response to polymyxin treatments." Molecular Omics 16, no. 4 (2020): 327–38. http://dx.doi.org/10.1039/d0mo00015a.

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Our pan-transcriptomic study for polymyxin-treated A. baumannii identified that the remodelled outer membrane, up-regulated efflux pumps and down-regulated fatty acid biosynthesis might be essential for early responses to polymyxins in A. baumannii.

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Ou, Yaqing, and James O. McInerney. "Eukaryote Genes Are More Likely than Prokaryote Genes to Be Composites." Genes 10, no. 9 (August 28, 2019): 648. http://dx.doi.org/10.3390/genes10090648.

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The formation of new genes by combining parts of existing genes is an important evolutionary process. Remodelled genes, which we call composites, have been investigated in many species, however, their distribution across all of life is still unknown. We set out to examine the extent to which genomes from cells and mobile genetic elements contain composite genes. We identify composite genes as those that show partial homology to at least two unrelated component genes. In order to identify composite and component genes, we constructed sequence similarity networks (SSNs) of more than one million genes from all three domains of life, as well as viruses and plasmids. We identified non-transitive triplets of nodes in this network and explored the homology relationships in these triplets to see if the middle nodes were indeed composite genes. In total, we identified 221,043 (18.57%) composites genes, which were distributed across all genomic and functional categories. In particular, the presence of composite genes is statistically more likely in eukaryotes than prokaryotes.

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Kuleesha, Yadav, Wee Choo Puah, and Martin Wasser. "A model of muscle atrophy based on live microscopy of muscle remodelling in Drosophila metamorphosis." Royal Society Open Science 3, no. 2 (February 2016): 150517. http://dx.doi.org/10.1098/rsos.150517.

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Genes controlling muscle size and survival play important roles in muscle wasting diseases. In Drosophila melanogaster metamorphosis, larval abdominal muscles undergo two developmental fates. While a doomed population is eliminated by cell death, another persistent group is remodelled and survives into adulthood. To identify and characterize genes involved in the development of remodelled muscles, we devised a workflow consisting of in vivo imaging, targeted gene perturbation and quantitative image analysis. We show that inhibition of TOR signalling and activation of autophagy promote developmental muscle atrophy in early, while TOR and yorkie activation are required for muscle growth in late pupation. We discovered changes in the localization of myonuclei during remodelling that involve anti-polar migration leading to central clustering followed by polar migration resulting in localization along the midline. We demonstrate that the Cathepsin L orthologue Cp1 is required for myonuclear clustering in mid, while autophagy contributes to central positioning of nuclei in late metamorphosis. In conclusion, studying muscle remodelling in metamorphosis can provide new insights into the cell biology of muscle wasting.

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Wang, Yuzhe, Shiyu Li, Mengge Liu, Jiajia Wang, Zhengbin Fei, Feng Wang, Zhenyou Jiang, Wenhua Huang, and Hanxiao Sun. "Rhodosporidium toruloides sir2-like genes remodelled the mitochondrial network to improve the phenotypes of ageing cells." Free Radical Biology and Medicine 134 (April 2019): 64–75. http://dx.doi.org/10.1016/j.freeradbiomed.2018.12.036.

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Ahmedien, Diaa Ahmed Mohamed. "Bio-pixels: A stem cell-based interactive–generative interface designed to redefine technologies of self-making in new media arts." Convergence: The International Journal of Research into New Media Technologies 26, no. 5-6 (November 29, 2019): 1367–90. http://dx.doi.org/10.1177/1354856519890096.

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Bio-pixels is a stem cell-based interactive–generative interface designed to investigate the concept of ‘self-making’. The project uses stem cells as a biological prototype of an identity-free substance and defines in vivo stem cell differentiation processes as nature’s self-making technology. It therefore considers in vitro-induced differentiation processes as artificial self-making technologies that were recontextualized through the interactions between the world of genes and the world of bits. The project’s system was functionally built based on three operational principles derived from convergence technologies that facilitate a mutual functional shift between bio-media and digital media and reveal the extent to which this shift leads to a reconciliation between our biological and narrative identities. Empirically, the project remodelled visual maps of cellular activities during the induced differentiation processes by which cells acquire their identity. Finally, a generative biological–digital mirror was architected by which the viewers see their faces resynthesized as the result of the interactions between the artificial remodelled differentiation processes and the participants’ activities at the project’s physical place and its Twitter page. Within this context, Bio-pixels highlights the consequences of today’s bioinformatics on in vitro artificial processes of self-making through which the public can control, enhance or resynthesize their identities.

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Dalla Torre, Marco, Daniele Pittari, Alessandra Boletta, Laura Cassina, Roberto Sitia, and Tiziana Anelli. "Mitochondria remodeling during endometrial stromal cell decidualization." Life Science Alliance 7, no. 12 (October 4, 2024): e202402627. http://dx.doi.org/10.26508/lsa.202402627.

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Upon hormonal stimulation, uterine endometrial stromal cells undergo a dramatic morpho-functional metamorphosis that allows them to secrete large amounts of matrix proteins, cytokines, and growth factors. This step, known as decidualization, is crucial for embryo implantation. We previously demonstrated how the secretory pathway is remodelled during this process. Here we show that hormonal stimulation rapidly induces the expression of many mitochondrial genes, encoded in both the mitochondrial and the nuclear genomes. Altogether, the mitochondrial network quadruples its size and establishes more contacts with the ER. This new organization results in the increased respiratory capacity of decidualized cells. These findings reveal how achieving an efficient secretory phenotype requires a radical metabolic rewiring.

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Reik, Wolf, Fatima Santos, Kohzoh Mitsuya, Hugh Morgan, and Wendy Dean. "Epigenetic asymmetry in the mammalian zygote and early embryo: relationship to lineage commitment?" Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 358, no. 1436 (August 29, 2003): 1403–9. http://dx.doi.org/10.1098/rstb.2003.1326.

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Epigenetic asymmetry between parental genomes and embryonic lineages exists at the earliest stages of mammalian development. The maternal genome in the zygote is highly methylated in both its DNA and its histones and most imprinted genes have maternal germline methylation imprints. The paternal genome is rapidly remodelled with protamine removal, addition of acetylated histones, and rapid demethylation of DNA before replication. A minority of imprinted genes have paternal germline methylation imprints. Methylation and chromatin reprogramming continues during cleavage divisions, but at the blastocyst stage lineage commitment to inner cell mass (ICM) or trophectoderm (TE) fate is accompanied by a dramatic increase in DNA and histone methylation, predominantly in the ICM. This may set up major epigenetic differences between embryonic and extraembryonic tissues, including in X–chromosome inactivation and perhaps imprinting. Maintaining epigenetic asymmetry appears important for development as asymmetry is lost in cloned embryos, most of which have developmental defects, and in particular an imbalance between extraembryonic and embryonic tissue development.

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Chen, Xinxin, Jun Wang, Donna Woltring, Steve Gerondakis, and M. Frances Shannon. "Histone Dynamics on the Interleukin-2 Gene in Response to T-Cell Activation." Molecular and Cellular Biology 25, no. 8 (April 15, 2005): 3209–19. http://dx.doi.org/10.1128/mcb.25.8.3209-3219.2005.

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ABSTRACT Several models have been proposed for the mechanism of chromatin remodelling across the promoters of inducible genes in mammalian cells. The most commonly held model is one of cooccupation where histone proteins are modified by acetylation or phosphorylation and nucleosomes are remodelled, allowing the assembly of transcription factor complexes. Using chromatin immunoprecipitation, we observed an apparent decrease of histone acetylation and phosphorylation signals at the proximal promoter region of the inducible interleukin-2 and granulocyte-macrophage colony-stimulating factor genes in response to T-cell activation. We showed that this apparent decrease was due to a loss of histone H3 and H4 proteins corresponding to a decrease in nucleosome occupation of the promoter. This histone loss is reversible; it is dependent on the continual presence of appropriate activating signals and transcription factors and is not dependent on the acetylation status of the histone proteins. These data show for the first time that histone proteins are lost from a mammalian promoter upon activation of transcription and support a model of activation-dependent disassembly and reassembly of nucleosomes.

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PRAJAPATI, SURENDRA K., RICHARD CULLETON, and OM P. SINGH. "Protein trafficking in Plasmodium falciparum-infected red cells and impact of the expansion of exported protein families." Parasitology 141, no. 12 (July 30, 2014): 1533–43. http://dx.doi.org/10.1017/s0031182014000948.

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SUMMARYErythrocytes are extensively remodelled by the malaria parasite following invasion of the cell. Plasmodium falciparum encodes numerous virulence-associated and host-cell remodelling proteins that are trafficked to the cytoplasm, the cell membrane and the surface of the infected erythrocyte. The export of soluble proteins relies on a sequence directing entry into the secretory pathways in addition to an export signal. The export signal consisting of five amino acids is termed the Plasmodium export element (PEXEL) or the vacuole transport signal (VTS). Genome mining studies have revealed that PEXEL/VTS carrying protein families have expanded dramatically in P. falciparum compared with other malaria parasite species, possibly due to lineage-specific expansion linked to the unique requirements of P. falciparum for host-cell remodelling. The functional characterization of such genes and gene families may reveal potential drug targets that could inhibit protein trafficking in infected erythrocytes. This review highlights some of the recent advances and key knowledge gaps in protein trafficking pathways in P. falciparum-infected red cells and speculates on the impact of exported gene families in the trafficking pathway.

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Boudin, Eveline, and Wim Van Hul. "MECHANISMS IN ENDOCRINOLOGY: Genetics of human bone formation." European Journal of Endocrinology 177, no. 2 (August 2017): R69—R83. http://dx.doi.org/10.1530/eje-16-0990.

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Throughout life, bone is continuously remodelled to be able to fulfil its multiple functions. The importance of strictly regulating the bone remodelling process, which is defined by the sequential actions of osteoclasts and osteoblasts, is shown by a variety of disorders with abnormalities in bone mass and strength. The best known and most common example of such a disorder is osteoporosis, which is marked by a decreased bone mass and strength that consequently results in an increased fracture risk. As osteoporosis is a serious health problem, a large number of studies focus on elucidating the aetiology of the disease as well as on the identification of novel therapeutic targets for the treatment of osteoporotic patients. These studies have demonstrated that a large amount of variation in bone mass and strength is often influenced by genetic variation in genes encoding important regulators of bone homeostasis. Throughout the years, studies into the genetic causes of osteoporosis as well as several rare monogenic disorders with abnormal high or low bone mass and strength have largely increased the knowledge on regulatory pathways important for bone resorption and formation. This review gives an overview of genes and pathways that are important for the regulation of bone formation and that are identified through their involvement in monogenic and complex disorders with abnormal bone mass. Furthermore, novel bone-forming strategies for the treatment of osteoporosis that resulted from these discoveries, such as antibodies against sclerostin, are discussed as well.

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Wood, W., M. Turmaine, R. Weber, V. Camp, R. A. Maki, S. R. McKercher, and P. Martin. "Mesenchymal cells engulf and clear apoptotic footplate cells in macrophageless PU.1 null mouse embryos." Development 127, no. 24 (December 15, 2000): 5245–52. http://dx.doi.org/10.1242/dev.127.24.5245.

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Apoptosis is one of the key tools used by an embryo to regulate cell numbers and sculpt body shape. Although massive numbers of cells die during development, they are so rapidly phagocytosed that very few corpses are ever seen in most embryonic tissues. In this paper, we focus on the catastrophic cell death that occurs as the developing footplate is remodelled to transform webbed regions into free interdigital spaces. In the wild-type embryo, these dead cells are rapidly engulfed and cleared by macrophages. We show that in a macrophageless mouse embryo, null for the haemopoetic-lineage-specific transcription factor, PU.1, the task of phagocytosis is taken over by ‘stand-in’ mesenchymal neighbours in a clear example of cell redundancy. However, it takes three times as many of these mesenchymal phagocytes to complete the task and, at each stage of the clearance process - in the recognition of apoptotic debris, its engulfment and finally its digestion - they appear to be less efficient than macrophages. A molecular explanation for this may be that several of the engulfment genes expressed by macrophages, including the ABC1 transporter (believed to be part of the phagocytic machinery conserved from Caenorhabditis elegans to mouse), are not upregulated by these ‘stand-in’ phagocytes.

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Farrell, K., K. Uh, and K. Lee. "45 Expression patterns of PRDM family genes in porcine pre-implantation embryos." Reproduction, Fertility and Development 32, no. 2 (2020): 148. http://dx.doi.org/10.1071/rdv32n2ab45.

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Establishing proper levels of pluripotency is essential for normal development. The genome of gametes is remodelled upon fertilisation and pluripotency-related genes are expressed in blastocysts. Multiple pluripotency-related genes are involved in the well-orchestrated process; however, detailed mechanistic actions remain elusive. The PRDM family genes are reported to be closely related to the pluripotency. A previous report noted that PRDM14 plays an important role in the maintenance of pluripotency in human embryonic stem cells (ESCs) and potentially murine ESCs; loss of PRDM14 was found to cause abnormalities in genome-wide epigenetic status. Similarly, PRDM15 was found to be a key regulator of pluripotency in mouse ESCs. Structural similarities among the PRDM family suggest that other PRDM family genes may help to establish and maintain pluripotency in embryos. Unfortunately, little is known about the expression profile of PRDM family in porcine embryos. To expand our understanding of the role of PRDM family in porcine embryos, expression patterns of PRDM gene family were investigated using reverse transcription quantitative (RTq)-PCR. Candidate PRDM family genes were selected based on previous RNA-Seq data in porcine oocytes/embryos. To conduct this study, germinal vesicle (GV), MII, zygote, 4-cell, and blastocyst samples were collected. Complementary DNA synthesised from the samples was used for RT-qPCR to analyse the expression pattern of selected PRDM family genes: PRDM2, PRDM4, PRDM6, PRDM14, and PRDM15. The expression of target genes was normalized to the YWHAG level, an internal control. Then, GV stage was used as a control for ΔΔCT analysis. Two technical replications and three biological replications were performed. Analysis of variance was used for statistical analysis and P-values<0.05 were considered significant. There was a significant decrease in PRDM2 expression in 4-cell and blastocyst, PRDM4 expression in 4-cell, and PRDM6 in all stages (MII, zygote, 4-cell, and blastocyst), compared with the GV stage. Because zygotic genome activation occurs at the 4-cell stage in the pig, the significant decrease in gene expression (PRDM2, PRDM4, and PRDM6) indicates they may be maternally originated and involved in the reprogramming process following fertilisation. On the other hand, there was a significant increase in PRDM15 expression in blastocysts and the PRDM14 transcript was only detected in blastocysts in all three biological replicates, suggesting that the genes are most likely involved in pluripotency maintenance, as was found in previous human studies. These results indicate that PRDM family genes are differentially expressed during early embryo development in pigs and may play a role in maintenance of pluripotency. For further study, we intend to evaluate the role of PRDM family genes during early embryo development in pigs.

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Paino, Francesca, Marcella La Noce, Alessandra Giuliani, Alfredo De Rosa, Serena Mazzoni, Luigi Laino, Evzen Amler, Gianpaolo Papaccio, Vincenzo Desiderio, and Virginia Tirino. "Human DPSCs fabricate vascularized woven bone tissue: a new tool in bone tissue engineering." Clinical Science 131, no. 8 (April 6, 2017): 699–713. http://dx.doi.org/10.1042/cs20170047.

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Human dental pulp stem cells (hDPSCs) are mesenchymal stem cells that have been successfully used in human bone tissue engineering. To establish whether these cells can lead to a bone tissue ready to be grafted, we checked DPSCs for their osteogenic and angiogenic differentiation capabilities with the specific aim of obtaining a new tool for bone transplantation. Therefore, hDPSCs were specifically selected from the stromal–vascular dental pulp fraction, using appropriate markers, and cultured. Growth curves, expression of bone-related markers, calcification and angiogenesis as well as an in vivo transplantation assay were performed. We found that hDPSCs proliferate, differentiate into osteoblasts and express high levels of angiogenic genes, such as vascular endothelial growth factor and platelet-derived growth factor A. Human DPSCs, after 40 days of culture, give rise to a 3D structure resembling a woven fibrous bone. These woven bone (WB) samples were analysed using classic histology and synchrotron-based, X-ray phase-contrast microtomography and holotomography. WB showed histological and attractive physical qualities of bone with few areas of mineralization and neovessels. Such WB, when transplanted into rats, was remodelled into vascularized bone tissue. Taken together, our data lead to the assumption that WB samples, fabricated by DPSCs, constitute a noteworthy tool and do not need the use of scaffolds, and therefore they are ready for customized regeneration.

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Ben-Aicha, Soumaya, Rafael Escate, Laura Casaní, Teresa Padró, Esther Peña, Gemma Arderiu, Guiomar Mendieta, Lina Badimón, and Gemma Vilahur. "High-density lipoprotein remodelled in hypercholesterolaemic blood induce epigenetically driven down-regulation of endothelial HIF-1α expression in a preclinical animal model." Cardiovascular Research 116, no. 7 (August 30, 2019): 1288–99. http://dx.doi.org/10.1093/cvr/cvz239.

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Abstract Aims High-density lipoproteins (HDLs) are circulating micelles that transport proteins, lipids, and miRNAs. HDL-transported miRNAs (HDL-miRNAs) have lately received attention but their effects on vascular cells are not fully understood. Additionally, whether cardiovascular risk factors affect HDL-miRNAs levels and miRNA transfer to recipient cells remains equally poorly known. Here, we have investigated the changes induced by hypercholesterolaemia on HDL-miRNA levels and its effect on recipient endothelial cells (ECs). Methods and results Pigs were kept on a high-fat diet (HC; n = 10) or a normocholesterolaemic chow (NC; n = 10) for 10 days reaching cholesterol levels of 321.0 (229.7–378.5) mg/dL and 74.0 (62.5–80.2) mg/dL, respectively. HDL particles were isolated, purified, and quantified. HDL-miRNA profiling (n = 149 miRNAs) of HC- and NC-HDLs was performed by multipanel qPCR. Cell cultures of porcine aortic ECs were used to determine whether HDL-miRNAs were delivered to ECs. Potential target genes modulated by miRNAs were identified by bioinformatics and candidate miRNAs were validated by molecular analysis. In vivo effects in the coronary arteries of normocholesterolaemic swine administered HC- or NC-HDLs were analysed. Among the HDL-miRNAs, four were found in different amounts in HC- and NC-HDL (P < 0.05). miR-126-5p and -3p and miR-30b-5p (2.7×, 1.7×, and 1.3×, respectively) were found in higher levels and miR-103a-3p and miR-let-7g-5p (−1.6×, −1.4×, respectively) in lower levels in HC-HDL. miR-126-5p and -3p were transferred from HC-HDL to EC (2.5×; P < 0.05), but not from NC-HDL, by a SRB1-mediated mechanism. Bioinformatics revealed that HIF1α was the miR-126 target gene with the highest predictive value, which was accordingly found to be markedly reduced in HC-HDL-treated ECs and in miR126 mimic transfected ECs. In vivo validation confirmed that HIF1α was diminished in the coronary endothelial layer of NC pigs administered HC-HDL vs. those administered NC-HDL (P < 0.05). Conclusion Hypercholesterolaemia induces changes in the miRNA content of HDL enhancing miR126 and its delivery to ECs with the consequent down-regulation of its target gene HIF1α.

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VINCENTI, Matthew P., Charles I. COON, J. Andrew MENGSHOL, Sue YOCUM, Peter MITCHELL, and Constance E. BRINCKERHOFF. "Cloning of the gene for interstitial collagenase-3 (matrix metalloproteinase-13) from rabbit synovial fibroblasts: differential expression with collagenase-1 (matrix metalloproteinase-1)." Biochemical Journal 331, no. 1 (April 1, 1998): 341–46. http://dx.doi.org/10.1042/bj3310341.

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Cartilage, bone and the interstitial stroma, composed largely of the interstitial collagens, types I, II and III, are remodelled by three members of the metalloproteinase (MMP) family, collagenase-1 (MMP-1), collagenase-2 (MMP-8) and collagenase-3 (MMP-13). MMP-1 and MMP-13 may contribute directly to disease progression, since they are induced in patients with rheumatoid arthritis and osteoarthritis. The study of MMP-1 and MMP-13 gene regulation in models of arthritic disease has been problematic because mice and rats, which are typically used, only possess a homologue of MMP-13. Here we show that in contrast with mice and rats, rabbits possess distinct genes homologous to human MMP-1 and MMP-13. Furthermore, rabbit MMP-13 is expressed simultaneously with MMP-1 in chondrocytes and synovial fibroblasts in response to the cytokines interleukin-1 and tumour necrosis factor-α, or the phorbol ester PMA. The time course of MMP-13 induction is more rapid and transient than that of MMP-1, suggesting that distinct mechanisms regulate the expression of these two collagenases. We have cloned the rabbit MMP-13 gene from synovial fibroblasts and demonstrated that the rabbit gene shares greater homology with human MMP-13 than does the mouse interstitial collagenase. Together with the fact that mice and rats do not possess a homologue to human MMP-1, our data suggest that the rabbit provides an appropriate model for studying the roles of interstitial collagenases in connective-tissue diseases, such as rheumatoid arthritis and osteoarthritis.

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Koenning, Matthias, Xianlong Wang, Menuka Karki, Rahul Kumar Jangid, Sarah Kearns, Durga Nand Tripathi, Michael Cianfrocco, et al. "Neuronal SETD2 activity links microtubule methylation to an anxiety-like phenotype in mice." Brain 144, no. 8 (May 20, 2021): 2527–40. http://dx.doi.org/10.1093/brain/awab200.

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Abstract Gene discovery efforts in autism spectrum disorder have identified heterozygous defects in chromatin remodeller genes, the ‘readers, writers and erasers’ of methyl marks on chromatin, as major contributors to this disease. Despite this advance, a convergent aetiology between these defects and aberrant chromatin architecture or gene expression has remained elusive. Recently, data have begun to emerge that chromatin remodellers also function directly on the cytoskeleton. Strongly associated with autism spectrum disorder, the SETD2 histone methyltransferase for example, has now been shown to directly methylate microtubules of the mitotic spindle. However, whether microtubule methylation occurs in post-mitotic cells, for example on the neuronal cytoskeleton, is not known. We found the SETD2 α-tubulin lysine 40 trimethyl mark occurs on microtubules in the brain and in primary neurons in culture, and that the SETD2 C-terminal SRI domain is required for binding and methylation of α-tubulin. A CRISPR knock-in of a pathogenic SRI domain mutation (Setd2SRI) that disables microtubule methylation revealed at least one wild-type allele was required in mice for survival, and while viable, heterozygous Setd2SRI/wtmice exhibited an anxiety-like phenotype. Finally, whereas RNA-sequencing (RNA-seq) and chromatin immunoprecipitation-sequencing (ChIP-seq) showed no concomitant changes in chromatin methylation or gene expression in Setd2SRI/wtmice, primary neurons exhibited structural deficits in axon length and dendritic arborization. These data provide the first demonstration that microtubules of neurons are methylated, and reveals a heterozygous chromatin remodeller defect that specifically disables microtubule methylation is sufficient to drive an autism-associated phenotype.

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Ciciarello, Marilena, Francesca Girotti, Darina Ocadlikova, Letizia Zannoni, Federica Ardizzoia, Cecilia Evangelisti, Cesare Rossi, Michele Cavo, and Antonio Curti. "Interferon-Gamma Production By Dysplastic Cells Supports an Immune-Tolerant Bone Marrow Microenvironment in Myelodysplastic Syndrome Patients." Blood 144, Supplement 1 (November 5, 2024): 6687. https://doi.org/10.1182/blood-2024-203447.

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Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of haematological malignancies with a poor prognosis and a risk of evolving into acute myeloid leukaemia (AML). Besides intrinsic cellular defects, extrinsic microenvironmental factors, particularly inflammatory signals in the bone marrow (BM), play a crucial role in MDS progression. In AML, we demonstrated that leukemic cells produced interferon (IFN)γ, allowing us to stratify them in INFGhigh and IFNGlow samples. Higher IFNγ levels remodelled the BM microenvironment, favouring the indoleamine 2,3-dioxygenase (IDO)1-dependent induction of immunosuppressive Tregs associated with increased engraftment of leukemic cells in a mouse model. Furthermore, AML samples with increased IFNγ production showed downregulated expression of HLA class II genes, including CIITA (Class II major histocompatibility complex transactivator). Since leukemic cells with high CIITA methylation are resistant to HLA-dependent IFNγ up-regulation, CIITA methylation/HLA-downregulation could represent a further IFNγ-dependent mechanism of immune suppression. This study aims to explore Tregs induction and HLA down-regulation as putative IFNγ-dependent mechanisms of tolerance and immune escape in MDS, eventually favouring AML progression. Methods: We used quantitative real-time PCR and flow cytometry to characterize BM-derived MDS samples (N=22) at diagnosis. Results: MDS samples showed varying IFNγ levels, generally higher than in AML samples. MDS samples had more IFNγ-positive cells in the BM than IFNGlow AML samples, with dysplastic cells being the primary source of IFNγ, although CD3+, CD8+ T cells, and NK cells also contributed. Interestingly, we found a positive correlation between IFNγ and IDO1 expression at both mRNA and protein levels, suggesting an immune-tolerant microenvironment in MDS similar to AML. Next, MDS samples had a higher percentage of total Tregs than healthy donors and IFNGlow AML samples but lower than INFGhigh AML samples. Treg levels varied with MDS prognostic risk. MDS samples also exhibited different levels and patterns of HLA class II gene expression correlated with IFNγ, with some MDS samples holding an IFNγ-inducible HLA class II gene expression and others with a not-inducible HLA class II gene expression, suggesting a correlation with CIITA methylation grade. Summary/Conclusions: This study shows that IFNγ production by MDS cells remodels the BM landscape toward IDO1 upregulation, Treg induction and modulation of HLA class II gene expression, supporting the immune-tolerant role of inflammation, which is emerging as a critical aspect in AML prognosis and outcome and could be implied in MDS risk stratification and progression in AML.

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Farrell, Jeffrey A., and Patrick H. O'Farrell. "From Egg to Gastrula: How the Cell Cycle Is Remodeled During theDrosophilaMid-Blastula Transition." Annual Review of Genetics 48, no. 1 (November 23, 2014): 269–94. http://dx.doi.org/10.1146/annurev-genet-111212-133531.

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Norton, Kacie A., Ross Humphreys, Chelsey Weatherill, Kevin Duong, Vivian V. Nguyen, Arun Kommadath, Farshad Niri, Paul Stothard, and Heather E. McDermid. "Subfertility in young male mice mutant for chromatin remodeller CECR2." Reproduction 163, no. 2 (February 1, 2022): 69–83. http://dx.doi.org/10.1530/rep-19-0507.

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Defects in spermatogenesis are an important cause of male infertility. Multiple aspects of spermatogenesis are controlled by chromatin remodellers, including regulating transcription. We previously described mutations in chromatin remodelling gene Cecr2 that resulted in the lethal neural tube defect exencephaly in most mutant mice and subfertility in mice that were non-penetrant for exencephaly. Here, we show that the severity of male subfertility is dependent on age. Cecr2GT/Del males contain two mutant alleles, one of which is hypomorphic and therefore produces a small amount of protein. These males sire the fewest pups just after sexual maturity (88% fewer than Cecr2+/+ at P42–60) but improve with age (49% fewer than Cecr2+/+ at P81–100), although never completely recovering to Cecr2+/+(wild type) levels. When young, they also have defects in testis histology, in vivo fertilization frequency, sperm number and motility, and testis weight that show similar improvement with age. Immunostaining of staged seminiferous tubules showed CECR2 in type A, intermediate and B spermatogonia, and less in preleptotene and leptotene spermatocytes. Histological defects were first apparent in Cecr2GT/Del testes at P24, and RNA-seq analysis revealed 387 differentially expressed genes. This included 66 genes on the X chromosome (almost double the number on any other chromosome), all more highly expressed in Cecr2GT/Del testes. This inappropriate expression of X chromosome genes could be caused by a failure of effective meiotic sex chromosome inactivation. We identify several abnormally expressed genes that may contribute to defects in spermatogenesis at P24. Our results support a role for Cecr2 in juvenile spermatogenesis.

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González-Medina, Alberto, Esther Pazo, Elena Hidalgo, and José Ayté. "SWI/SNF and RSC remodeler complexes bind to MBF-dependent genes." Cell Cycle 20, no. 24 (November 29, 2021): 2652–61. http://dx.doi.org/10.1080/15384101.2021.2008203.

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Loesch, Robin, Linda Chenane, and Sabine Colnot. "ARID2 Chromatin Remodeler in Hepatocellular Carcinoma." Cells 9, no. 10 (September 23, 2020): 2152. http://dx.doi.org/10.3390/cells9102152.

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Chromatin remodelers are found highly mutated in cancer including hepatocellular carcinoma. These mutations frequently occur in ARID (AT-rich Interactive Domain) genes, encoding subunits of the ATP-dependent SWI/SNF remodelers. The increasingly prevalent complexity that surrounds the functions and specificities of the highly modular BAF (BG1/BRM-associated factors) and PBAF (polybromo-associated BAF) complexes, including ARID1A/B or ARID2, is baffling. The involvement of the SWI/SNF complexes in diverse tissues and processes, and especially in the regulation of gene expression, multiplies the specific outcomes of specific gene alterations. A better understanding of the molecular consequences of specific mutations impairing chromatin remodelers is needed. In this review, we summarize what we know about the tumor-modulating properties of ARID2 in hepatocellular carcinoma.

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Poli, Jérôme, Susan M. Gasser, and Manolis Papamichos-Chronakis. "The INO80 remodeller in transcription, replication and repair." Philosophical Transactions of the Royal Society B: Biological Sciences 372, no. 1731 (August 28, 2017): 20160290. http://dx.doi.org/10.1098/rstb.2016.0290.

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The accessibility of eukaryotic genomes to the action of enzymes involved in transcription, replication and repair is maintained despite the organization of DNA into nucleosomes. This access is often regulated by the action of ATP-dependent nucleosome remodellers. The INO80 class of nucleosome remodellers has unique structural features and it is implicated in a diverse array of functions, including transcriptional regulation, DNA replication and DNA repair. Underlying these diverse functions is the catalytic activity of the main ATPase subunit, which in the context of a multisubunit complex can shift nucleosomes and carry out histone dimer exchange. In vitro studies showed that INO80 promotes replication fork progression on a chromatin template, while in vivo it was shown to facilitate replication fork restart after stalling and to help evict RNA polymerase II at transcribed genes following the collision of a replication fork with transcription. More recent work in yeast implicates INO80 in the general eviction and degradation of nucleosomes following high doses of oxidative DNA damage. Beyond these replication and repair functions, INO80 was shown to repress inappropriate transcription at promoters in the opposite direction to the coding sequence. Here we discuss the ways in which INO80's diverse functions help maintain genome integrity. This article is part of the themed issue ‘Chromatin modifiers and remodellers in DNA repair and signalling’.

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Soutourina, Julie, Véronique Bordas-Le Floch, Gabrielle Gendrel, Amando Flores, Cécile Ducrot, Hélène Dumay-Odelot, Pascal Soularue, et al. "Rsc4 Connects the Chromatin Remodeler RSC to RNA Polymerases." Molecular and Cellular Biology 26, no. 13 (July 1, 2006): 4920–33. http://dx.doi.org/10.1128/mcb.00415-06.

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ABSTRACT RSC is an essential, multisubunit chromatin remodeling complex. We show here that the Rsc4 subunit of RSC interacted via its C terminus with Rpb5, a conserved subunit shared by all three nuclear RNA polymerases (Pol). Furthermore, the RSC complex coimmunoprecipitated with all three RNA polymerases. Mutations in the C terminus of Rsc4 conferred a thermosensitive phenotype and the loss of interaction with Rpb5. Certain thermosensitive rpb5 mutations were lethal in combination with an rsc4 mutation, supporting the physiological significance of the interaction. Pol II transcription of ca. 12% of the yeast genome was increased or decreased twofold or more in a rsc4 C-terminal mutant. The transcription of the Pol III-transcribed genes SNR6 and RPR1 was also reduced, in agreement with the observed localization of RSC near many class III genes. Rsc4 C-terminal mutations did not alter the stability or assembly of the RSC complex, suggesting an impact on Rsc4 function. Strikingly, a C-terminal mutation of Rsc4 did not impair RSC recruitment to the RSC-responsive genes DUT1 and SMX3 but rather changed the chromatin accessibility of DNases to their promoter regions, suggesting that the altered transcription of DUT1 and SMX3 was the consequence of altered chromatin remodeling.

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Subtil-Rodríguez, Alicia, Elena Vázquez-Chávez, María Ceballos-Chávez, Manuel Rodríguez-Paredes, José I. Martín-Subero, Manel Esteller, and José C. Reyes. "The chromatin remodeller CHD8 is required for E2F-dependent transcription activation of S-phase genes." Nucleic Acids Research 42, no. 4 (November 20, 2013): 2185–96. http://dx.doi.org/10.1093/nar/gkt1161.

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Abstract The precise regulation of S-phase–specific genes is critical for cell proliferation. How the repressive chromatin configuration mediated by the retinoblastoma protein and repressor E2F factors changes at the G1/S transition to allow transcription activation is unclear. Here we show ChIP-on-chip studies that reveal that the chromatin remodeller CHD8 binds ∼2000 transcriptionally active promoters. The spectrum of CHD8 target genes was enriched in E2F-dependent genes. We found that CHD8 binds E2F-dependent promoters at the G1/S transition but not in quiescent cells. Consistently, CHD8 was required for G1/S-specific expression of these genes and for cell cycle re-entry on serum stimulation of quiescent cells. We also show that CHD8 interacts with E2F1 and, importantly, loading of E2F1 and E2F3, but not E2F4, onto S-specific promoters, requires CHD8. However, CHD8 recruiting is independent of these factors. Recruiting of MLL histone methyltransferase complexes to S-specific promoters was also severely impaired in the absence of CHD8. Furthermore, depletion of CHD8 abolished E2F1 overexpression-dependent S-phase stimulation of serum-starved cells, highlighting the essential role of CHD8 in E2F-dependent transcription activation.

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Chutani, Namita, Sandhya Ragula, Khajamohiddin Syed, and Suresh B. Pakala. "Novel Insights into the Role of Chromatin Remodeler MORC2 in Cancer." Biomolecules 13, no. 10 (October 15, 2023): 1527. http://dx.doi.org/10.3390/biom13101527.

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A newly discovered chromatin remodeler, MORC2, is a Microrchidia (MORC) family member. MORC2 acts as a chromatin remodeler by binding to the DNA and changing chromatin conformation using its ATPase domain. MORC2 is highly expressed in a variety of human cancers. It controls diverse signaling pathways essential for cancer development through its target genes and interacting partners. MORC2 promotes cancer cells’ growth, invasion, and migration by regulating the expression of genes involved in these processes. MORC2 is localized primarily in the nucleus and is also found in the cytoplasm. In the cytoplasm, MORC2 interacts with adenosine triphosphate (ATP)-citrate lyase (ACLY) to promote lipogenesis and cholesterogenesis in cancer. In the nucleus, MORC2 interacts with the transcription factor c-Myc to control the transcription of genes involved in glucose metabolism to drive cancer cell migration and invasion. Furthermore, MORC2 recruits on to the promoters of tumor suppressor genes to repress their transcription and expression to promote oncogenesis. In addition to its crucial function in oncogenesis, it plays a vital role in DNA repair. Overall, this review concisely summarizes the current knowledge about MORC2-regulated molecular pathways involved in cancer.

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Song, Yawei, Zhengyu Liang, Jie Zhang, Gongcheng Hu, Juehan Wang, Yaoyi Li, Rong Guo, et al. "CTCF functions as an insulator for somatic genes and a chromatin remodeler for pluripotency genes during reprogramming." Cell Reports 39, no. 1 (April 2022): 110626. http://dx.doi.org/10.1016/j.celrep.2022.110626.

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Yao, Wei, Devin A. King, Sean L. Beckwith, Graeme J. Gowans, Kuangyu Yen, Coral Zhou, and Ashby J. Morrison. "The INO80 Complex Requires the Arp5-Ies6 Subcomplex for Chromatin Remodeling and Metabolic Regulation." Molecular and Cellular Biology 36, no. 6 (January 11, 2016): 979–91. http://dx.doi.org/10.1128/mcb.00801-15.

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ATP-dependent chromatin remodeling complexes are essential for transcription regulation, and yet it is unclear how these multisubunit complexes coordinate their activities to facilitate diverse transcriptional responses. In this study, we found that the conserved Arp5 and Ies6 subunits of theSaccharomyces cerevisiaeINO80 chromatin-remodeler form an abundant and distinct subcomplexin vivoand stimulate INO80-mediated activityin vitro. Moreover, our genomic studies reveal that the relative occupancy of Arp5-Ies6 correlates with nucleosome positioning at transcriptional start sites and expression levels of >1,000 INO80-regulated genes. Notably, these genes are significantly enriched in energy metabolism pathways. Specifically,arp5Δ,ies6Δ, andino80Δ mutants demonstrate decreased expression of genes involved in glycolysis and increased expression of genes in the oxidative phosphorylation pathway. Deregulation of these metabolic pathways results in constitutively elevated mitochondrial potential and oxygen consumption. Our results illustrate the dynamic nature of the INO80 complex assembly and demonstrate for the first time that a chromatin remodeler regulates glycolytic and respiratory capacity, thereby maintaining metabolic stability.

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Bogliotti, Y. S., L. B. Ferré, D. J. Humpal, and P. J. Ross. "68 EPIGENETIC REMODELING OF HISTONE 3 MARKS DURING BOVINE PRE-IMPLANTATION DEVELOPMENT." Reproduction, Fertility and Development 26, no. 1 (2014): 148. http://dx.doi.org/10.1071/rdv26n1ab68.

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During pre-implantation development, substantial epigenetic changes occur that are thought to play key roles in achieving embryonic genome activation and totipotency. Embryonic genome activation occurs at the 8- to 16-cell stage in cattle and, although it is a crucial step of development, the specific mechanisms involved are still poorly understood. The aim of this study was to determine whether 4 histone 3 marks associated with active genes are remodelled during oocyte and early embryo development in cattle. The dynamics of acetylation of lysine 27 (H3K27ac), di-methylation of lysine 79 (H3K79me2), and mono- and tri-methylation of lysine 4 (H3K4me1, H3K4me3) were assessed by immunofluorescence and confocal microscopy. Ovaries were obtained from an abattoir. Immature germinal vesicle stage oocytes were aspirated from small antral follicles and matured for 24 h to the metaphase II stage (MII). Embryos were produced by in vitro fertilization and collected at different stages of development: pronuclear [PN; 18 h post-fertilization (hpf)], 2-cell (30 hpf), 4-cell (44 hpf), 8-cell (56 hpf), 16-cell (72 hpf), morula (120 hpf), and blastocyst (180 hpf). Three to 4 biological replicates were done per antibody and a total of 197 oocytes per embryo were imaged (8 to 16 per stage/antibody). The images were analysed using Fiji (Schindelin et al. 2012 Nat. Methods 9, 676–682). The average nuclear intensity per oocyte per embryo was adjusted by the average of 2 cytoplasmic areas (background). An ANOVA mixed model was used for statistical analysis using SAS (SAS Institute Inc., Cary, NC, USA). The least squares means of the different stages were compared (within each antibody group) using a Tukey-Kramer adjustment and were considered to be significantly different at P < 0.05. The H3K79me2 marks showed a significant increase from germinal vesicle to MII, a change opposite that of H3K27ac, which experienced a significant decrease between these two stages. The H3K4me1/me3 marks showed no significant changes during oocyte maturation. All 3 methylation marks presented a significant reduction in nuclear intensity from MII to PN, indicating that these marks are actively removed right after fertilization. The opposite effect was observed for the acetylation mark, in which the levels increased significantly from MII to PN. The H3K4me1/me3 marks showed a gradual decrease in intensity levels from the 2-cell stage onward, reaching a minimum at the 16-cell per morula stages. The H3K79me2 levels were low from PN to 16-cell stage, at which point its intensity levels began to increase, reaching statistical significance at the blastocyst stage. The H3K27ac marks showed a slow decrease in intensity levels from the PN stage, achieving statistical significance as it dropped to a minimum at the 16-cell stage. These results show that the global levels of the assayed epigenetic marks undergo dynamic changes during oocyte maturation and embryo development, suggesting that their remodelling may be important for early development. The authors thank Alta Genetics for providing the semen.

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Chohra, Ilyas, Keshi Chung, Subhajit Giri, and Brigitte Malgrange. "ATP-Dependent Chromatin Remodellers in Inner Ear Development." Cells 12, no. 4 (February 7, 2023): 532. http://dx.doi.org/10.3390/cells12040532.

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During transcription, DNA replication and repair, chromatin structure is constantly modified to reveal specific genetic regions and allow access to DNA-interacting enzymes. ATP-dependent chromatin remodelling complexes use the energy of ATP hydrolysis to modify chromatin architecture by repositioning and rearranging nucleosomes. These complexes are defined by a conserved SNF2-like, catalytic ATPase subunit and are divided into four families: CHD, SWI/SNF, ISWI and INO80. ATP-dependent chromatin remodellers are crucial in regulating development and stem cell biology in numerous organs, including the inner ear. In addition, mutations in genes coding for proteins that are part of chromatin remodellers have been implicated in numerous cases of neurosensory deafness. In this review, we describe the composition, structure and functional activity of these complexes and discuss how they contribute to hearing and neurosensory deafness.

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Yu, Xiaoming, Xinchao Meng, Yutong Liu, Ning Li, Ai Zhang, Tian-Jing Wang, Lili Jiang, et al. "The chromatin remodeler ZmCHB101 impacts expression of osmotic stress-responsive genes in maize." Plant Molecular Biology 97, no. 4-5 (June 28, 2018): 451–65. http://dx.doi.org/10.1007/s11103-018-0751-8.

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Morillon, Antonin. "Is histone loss a common feature of DNA metabolism regulation?This paper is one of a selection of papers published in this Special Issue, entitled 27th International West Coast Chromatin and Chromosome Conference, and has undergone the Journal's usual peer review process." Biochemistry and Cell Biology 84, no. 4 (August 2006): 450–52. http://dx.doi.org/10.1139/o06-070.

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Chromatin modifications play a crucial role in regulating DNA metabolism. Chromatin structures can be remodeled by covalently modifying histones, by shifting nucleosomes along the DNA, and by changing the histone composition of nucleosomes. Lately, nucleosome displacement has been extensively described within transcribed genes and DNA breaks. This review focuses on recently published work that describes the relationships between histone modification/exchange and nucleosome displacement.

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Feng, Ying, Yan Zhang, Zhiqing Lin, Xiaolei Ye, Xue Lin, Lixiu Lv, Yi Lin, Shenfei Sun, Yun Qi, and Xinhua Lin. "Chromatin remodeler Dmp18 regulates apoptosis by controlling H2Av incorporation in Drosophila imaginal disc development." PLOS Genetics 18, no. 9 (September 27, 2022): e1010395. http://dx.doi.org/10.1371/journal.pgen.1010395.

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Programmed Cell Death (PCD) or apoptosis is a highly conserved biological process and plays essential roles both in the development and stress context. In Drosophila, expression of pro-apoptotic genes, including reaper (rpr), head involution defective (hid), grim, and sickle (skl), is sufficient to induce cell death. Here, we demonstrate that the chromatin remodeler Dmp18, the homolog of mammalian Znhit1, plays a crucial role in regulating apoptosis in eye and wing development. We showed that loss of Dmp18 disrupted eye and wing development, up-regulated transcription of pro-apoptotic genes, and induced apoptosis. Inhibition of apoptosis suppressed the eye defects caused by Dmp18 deletion. Furthermore, loss of Dmp18 disrupted H2Av incorporation into chromatin, promoted H3K4me3, but reduced H3K27me3 modifications on the TSS regions of pro-apoptotic genes. These results indicate that Dmp18 negatively regulates apoptosis by mediating H2Av incorporation and histone H3 modifications at pro-apoptotic gene loci for transcriptional regulation. Our study uncovers the role of Dmp18 in regulating apoptosis in Drosophila eye and wing development and provides insights into chromatin remodeling regulating apoptosis at the epigenetic levels.

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Gidh-Jain, Madhavi, Boyu Huang, Praveer Jain, and Nabil El-Sherif. "Differential Expression of Voltage-Gated K+Channel Genes in Left Ventricular Remodeled Myocardium After Experimental Myocardial Infarction." Circulation Research 79, no. 4 (October 1996): 669–75. http://dx.doi.org/10.1161/01.res.79.4.669.

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Padilla-Benavides, Teresita, Monserrat Olea-Flores, Tapan Sharma, Sabriya A. Syed, Hanna Witwicka, Miriam D. Zuñiga-Eulogio, Kexin Zhang, Napoleon Navarro-Tito, and Anthony N. Imbalzano. "Differential Contributions of mSWI/SNF Chromatin Remodeler Sub-Families to Myoblast Differentiation." International Journal of Molecular Sciences 24, no. 14 (July 9, 2023): 11256. http://dx.doi.org/10.3390/ijms241411256.

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Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodeling enzymes that are critical for normal cellular functions. mSWI/SNF enzymes are classified into three sub-families based on the presence of specific subunit proteins. The sub-families are Brm- or Brg1-associated factor (BAF), ncBAF (non-canonical BAF), and polybromo-associated BAF (PBAF). The biological roles for the different enzyme sub-families are poorly described. We knocked down the expression of genes encoding unique subunit proteins for each sub-family, Baf250A, Brd9, and Baf180, which mark the BAF, ncBAF, and PBAF sub-families, respectively, and examined the requirement for each in myoblast differentiation. We found that Baf250A and the BAF complex were required to drive lineage-specific gene expression. KD of Brd9 delayed differentiation. However, while the Baf250A-dependent gene expression profile included myogenic genes, the Brd9-dependent gene expression profile did not, suggesting Brd9 and the ncBAF complex indirectly contributed to differentiation. Baf180 was dispensable for myoblast differentiation. The results distinguish between the roles of the mSWI/SNF enzyme sub-families during myoblast differentiation.

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Causton, Helen C., Bing Ren, Sang Seok Koh, Christopher T. Harbison, Elenita Kanin, Ezra G. Jennings, Tong Ihn Lee, Heather L. True, Eric S. Lander, and Richard A. Young. "Remodeling of Yeast Genome Expression in Response to Environmental Changes." Molecular Biology of the Cell 12, no. 2 (February 2001): 323–37. http://dx.doi.org/10.1091/mbc.12.2.323.

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We used genome-wide expression analysis to explore how gene expression in Saccharomyces cerevisiae is remodeled in response to various changes in extracellular environment, including changes in temperature, oxidation, nutrients, pH, and osmolarity. The results demonstrate that more than half of the genome is involved in various responses to environmental change and identify the global set of genes induced and repressed by each condition. These data implicate a substantial number of previously uncharacterized genes in these responses and reveal a signature common to environmental responses that involves ∼10% of yeast genes. The results of expression analysis with MSN2/MSN4 mutants support the model that the Msn2/Msn4 activators induce the common response to environmental change. These results provide a global description of the transcriptional response to environmental change and extend our understanding of the role of activators in effecting this response.

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Muñoz, Sofía, Francesca Passarelli, and Frank Uhlmann. "Conserved roles of chromatin remodellers in cohesin loading onto chromatin." Current Genetics 66, no. 5 (April 10, 2020): 951–56. http://dx.doi.org/10.1007/s00294-020-01075-x.

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Abstract Cohesin is a conserved, ring-shaped protein complex that topologically entraps DNA. This ability makes this member of the structural maintenance of chromosomes (SMC) complex family a central hub of chromosome dynamics regulation. Besides its essential role in sister chromatid cohesion, cohesin shapes the interphase chromatin domain architecture and plays important roles in transcriptional regulation and DNA repair. Cohesin is loaded onto chromosomes at centromeres, at the promoters of highly expressed genes, as well as at DNA replication forks and sites of DNA damage. However, the features that determine these binding sites are still incompletely understood. We recently described a role of the budding yeast RSC chromatin remodeler in cohesin loading onto chromosomes. RSC has a dual function, both as a physical chromatin receptor of the Scc2/Scc4 cohesin loader complex, as well as by providing a nucleosome-free template for cohesin loading. Here, we show that the role of RSC in sister chromatid cohesion is conserved in fission yeast. We discuss what is known about the broader conservation of the contribution of chromatin remodelers to cohesin loading onto chromatin.

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Reddy, B. Ashok, Prashanth Kumar Bajpe, Andrew Bassett, Yuri M. Moshkin, Elena Kozhevnikova, Karel Bezstarosti, Jeroen A. A. Demmers, Andrew A. Travers, and C. Peter Verrijzer. "Drosophila Transcription Factor Tramtrack69 Binds MEP1 To Recruit the Chromatin Remodeler NuRD." Molecular and Cellular Biology 30, no. 21 (August 23, 2010): 5234–44. http://dx.doi.org/10.1128/mcb.00266-10.

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ABSTRACT ATP-dependent chromatin-remodeling complexes (remodelers) are essential regulators of chromatin structure and gene transcription. How remodelers can act in a gene-selective manner has remained enigmatic. A yeast two-hybrid screen for proteins binding the Drosophila transcription factor Tramtrack69 (TTK69) identified MEP1. Proteomic characterization revealed that MEP1 is a tightly associated subunit of the NuRD remodeler, harboring the Mi2 enzymatic core ATPase. In addition, we identified the fly homolog of human Deleted in oral cancer 1 (DOC1), also known as CDK2-associated protein 1 (CDK2AP1), as a bona fide NuRD subunit. Biochemical and genetic assays supported the functional association between MEP1, Mi2, and TTK69. Genomewide expression analysis established that TTK69, MEP1, and Mi2 cooperate closely to control transcription. The TTK69 transcriptome profile correlates poorly with remodelers other than NuRD, emphasizing the selectivity of remodeler action. On the genes examined, TTK69 is able to bind chromatin in the absence of NuRD, but targeting of NuRD is dependent on TTK69. Thus, there appears to be a hierarchical relationship in which transcription factor binding precedes remodeler recruitment.

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Zhang, Heng, Brett Bishop, Whitney Ringenberg, William M. Muir, and Joe Ogas. "The CHD3 Remodeler PICKLE Associates with Genes Enriched for Trimethylation of Histone H3 Lysine 27." Plant Physiology 159, no. 1 (March 27, 2012): 418–32. http://dx.doi.org/10.1104/pp.112.194878.

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Poupeau, Audrey, Christian Garde, Karolina Sulek, Kiymet Citirikkaya, Jonas T. Treebak, Manimozhiyan Arumugam, David Simar, Louise E. Olofsson, Fredrik Bäckhed, and Romain Barrès. "Genes controlling the activation of natural killer lymphocytes are epigenetically remodeled in intestinal cells from germ‐free mice." FASEB Journal 33, no. 2 (October 10, 2018): 2719–31. http://dx.doi.org/10.1096/fj.201800787r.

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Melvin, Andrew, Sharon Mudie, and Sonia Rocha. "The chromatin remodeler ISWI regulates the cellular response to hypoxia: role of FIH." Molecular Biology of the Cell 22, no. 21 (November 2011): 4171–81. http://dx.doi.org/10.1091/mbc.e11-02-0163.

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The hypoxia-inducible factor (HIF) is a master regulator of the cellular response to hypoxia. Its levels and activity are controlled by dioxygenases called prolyl-hydroxylases and factor inhibiting HIF (FIH). To activate genes, HIF has to access sequences in DNA that are integrated in chromatin. It is known that the chromatin-remodeling complex switch/sucrose nonfermentable (SWI/SNF) is essential for HIF activity. However, no additional information exists about the role of other chromatin-remodeling enzymes in hypoxia. Here we describe the role of imitation switch (ISWI) in the cellular response to hypoxia. We find that unlike SWI/SNF, ISWI depletion enhances HIF activity without altering its levels. Furthermore, ISWI knockdown only alters a subset of HIF target genes. Mechanistically, we find that ISWI is required for full expression of FIH mRNA and protein levels by changing RNA polymerase II loading to the FIH promoter. Of interest, exogenous FIH can rescue the ISWI-mediated upregulation of CA9 but not BNIP3, suggesting that FIH-independent mechanisms are also involved. Of importance, ISWI depletion alters the cellular response to hypoxia by reducing autophagy and increasing apoptosis. These results demonstrate a novel role for ISWI as a survival factor during the cellular response to hypoxia.

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Crosswhite, Patrick L. "ATP-dependent chromatin remodeling complexes in embryonic vascular development and hypertension." American Journal of Physiology-Heart and Circulatory Physiology 317, no. 3 (September 1, 2019): H575—H580. http://dx.doi.org/10.1152/ajpheart.00147.2019.

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Hypertension, a chronic elevation in blood pressure, is the largest single contributing factor to mortality worldwide and the most common preventable risk factor for cardiovascular disease. High blood pressure increases the risk for someone to experience a number of adverse cardiovascular events including heart failure, stroke, or aneurysm. Despite advancements in understanding factors that contribute to hypertension, the etiology remains elusive and there remains a critical need to develop innovative study approaches to develop more effective therapeutics. ATP-dependent chromatin remodelers are dynamic regulators of DNA-histone bonds and thus gene expression. The goal of this review is to highlight and summarize reports of ATP-dependent chromatin remodelers contribution to the development or maintenance of hypertension. Emerging evidence from hypertensive animal models suggests that induction of chromatin remodeler activity increases proinflammatory genes and increases blood pressure, whereas human studies demonstrate how chromatin remodelers may act as stress-response sensors to harmful physiological stimuli. Importantly, genomic studies have linked patients with hypertension to mutations in chromatin remodeler genes. Collectively, evidence linking chromatin remodelers and hypertension warrants additional research and ultimately could reveal novel therapeutic approaches for treating this complex and devastating disease.

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Zhao, Haixin, Zhijun Han, Xinyuan Liu, Junjie Gu, Fan Tang, Gang Wei, and Ying Jin. "The chromatin remodeler Chd4 maintains embryonic stem cell identity by controlling pluripotency- and differentiation-associated genes." Journal of Biological Chemistry 292, no. 20 (March 15, 2017): 8507–19. http://dx.doi.org/10.1074/jbc.m116.770248.

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Li, Shitao, Lingyan Wang, Michael Berman, and Martin Dorf. "Mapping a dynamic innate immunity protein interaction network regulating type I interferon production (108.2)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 108.2. http://dx.doi.org/10.4049/jimmunol.188.supp.108.2.

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Abstract We use co-immunoprecipitation and mass spectrometry to identify antiviral signaling networks which regulate innate immune responses. Fifty-eight baits were associated with 260 interacting proteins forming a Human Innate Immunity Interactome of 401 unique interactions; 21% of interactions were remodeled following RNA, DNA, or LPS stimulation. Overexpression and depletion analyses identified 22 novel genes which regulate NF-kB and ISRE reporter activity, viral replication, or virus-induced interferon production. The innate immune interactome provides a dynamic physical and regulatory network which serves as a foundation for mechanistic analysis of antiviral signaling and links innate immunity with other cell processes.

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Walter, Korden, Constanze Bonifer, and Hiromi Tagoh. "Stem cell–specific epigenetic priming and B cell–specific transcriptional activation at the mouse Cd19 locus." Blood 112, no. 5 (September 1, 2008): 1673–82. http://dx.doi.org/10.1182/blood-2008-02-142786.

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Abstract Low-level expression of multiple lineage-specific genes is a hallmark of hematopoietic stem cells (HSCs). HSCs predominantly express genes specific for the myeloid or megakaryocytic-erythroid lineages, whereas the transcription of lymphoid specific genes appears to begin after lymphoid specification. It has been demonstrated for a number of genes that epigenetic priming occurs before gene expression and lineage specification; however, little is known about how epigenetic priming of lymphoid genes is regulated. To address the question of how B cell–restricted expression is established, we studied activation of the Cd19 gene during hematopoietic development. We identified a B cell–specific upstream enhancer and showed that the developmental regulation of Cd19 expression involves precisely coordinated alterations in transcription factor binding and chromatin remodeling at Cd19 cis-regulatory elements. In multipotent progenitor cells, Cd19 chromatin is first remodeled at the upstream enhancer, and this remodeling is associated with binding of E2A. This is followed by the binding of EBF and PAX5 during B-cell differentiation. The Cd19 promoter is transcriptionally activated only after PAX5 binding. Our experiments give important mechanistic insights into how widely expressed and B lineage–specific transcription factors cooperate to mediate the developmental regulation of lymphoid genes during hematopoiesis.

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Sperlazza, Justin, Mohamed Rahmani, Jason Beckta, Mandy Aust, Elisa Hawkins, Shou Zhen Wang, Sheng Zu Zhu, et al. "Depletion of the chromatin remodeler CHD4 sensitizes AML blasts to genotoxic agents and reduces tumor formation." Blood 126, no. 12 (September 17, 2015): 1462–72. http://dx.doi.org/10.1182/blood-2015-03-631606.

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Key Points CHD4 depletion sensitizes AML cells but not normal CD34+ progenitors to genotoxic agents by relaxing chromatin and impairing DSB repair. CHD4 depletion modulates expression of AML cell genes that regulate tumor formation in vivo and colony formation in vitro.

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Qiu, Hongfang, Emily Biernat, Chhabi K. Govind, Yashpal Rawal, Răzvan V. Chereji, David J. Clark, and Alan G. Hinnebusch. "Chromatin remodeler Ino80C acts independently of H2A.Z to evict promoter nucleosomes and stimulate transcription of highly expressed genes in yeast." Nucleic Acids Research 48, no. 15 (July 14, 2020): 8408–30. http://dx.doi.org/10.1093/nar/gkaa571.

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Abstract The chromatin remodelers SWI/SNF and RSC function in evicting promoter nucleosomes at highly expressed yeast genes, particularly those activated by transcription factor Gcn4. Ino80 remodeling complex (Ino80C) can establish nucleosome-depleted regions (NDRs) in reconstituted chromatin, and was implicated in removing histone variant H2A.Z from the −1 and +1 nucleosomes flanking NDRs; however, Ino80C’s function in transcriptional activation in vivo is not well understood. Analyzing the cohort of Gcn4-induced genes in ino80Δ mutants has uncovered a role for Ino80C on par with SWI/SNF in evicting promoter nucleosomes and transcriptional activation. Compared to SWI/SNF, Ino80C generally functions over a wider region, spanning the −1 and +1 nucleosomes, NDR and proximal genic nucleosomes, at genes highly dependent on its function. Defects in nucleosome eviction in ino80Δ cells are frequently accompanied by reduced promoter occupancies of TBP, and diminished transcription; and Ino80 is enriched at genes requiring its remodeler activity. Importantly, nuclear depletion of Ino80 impairs promoter nucleosome eviction even in a mutant lacking H2A.Z. Thus, Ino80C acts widely in the yeast genome together with RSC and SWI/SNF in evicting promoter nucleosomes and enhancing transcription, all in a manner at least partly independent of H2A.Z editing.

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Takahashi, I., M. Nishimura, K. Onodera, J. W. Bae, H. Mitani, M. Okazaki, Y. Sasano, and H. Mitani. "Expression of MMP-8 and MMP-13 Genes in the Periodontal Ligament during Tooth Movement in Rats." Journal of Dental Research 82, no. 8 (August 2003): 646–51. http://dx.doi.org/10.1177/154405910308200815.

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Periodontal ligament tissue is remodeled on both the tension and compression sides of moving teeth during orthodontic tooth movement. The present study was designed to clarify the hypothesis that the expression of MMP-8 and MMP-13 mRNA is promoted during the remodeling of periodontal ligament tissue in orthodontic tooth movement. We used the in situ hybridization method and semi-quantitative reverse-transcription/polymerase chain-reaction analysis to elucidate the gene expression of MMP-8 and MMP-13 mRNA. Expression of MMP-8 and MMP-13 mRNA transiently increased on both the compression and tension sides during active tooth movement in vivo. The gene expression of MMP-8 and MMP-13 was induced by tension, while compression indirectly promoted the gene expression of MMP-8 and MMP-13 through soluble factors in vitro. Thus, we concluded that the expression of MMP-8 and MMP-13 is differentially regulated by tension and compression, and plays an important role in the remodeling of the periodontal ligament.

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Zhang, Lijun, Zhenning Dai, Shanshan Shi, Zi Yan, Jiaxin Yang, Wanting Xue, Yunhao He, et al. "SIRT3 and SIRT4 double-genes remodeled the mitochondrial network to induce hepatocellular carcinoma cell line differentiation and suppress malignant phenotypes." Biochemical Pharmacology 223 (May 2024): 116168. http://dx.doi.org/10.1016/j.bcp.2024.116168.

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Iacobas, Dumitru Andrei, Ehiguese Alade Obiomon, and Sanda Iacobas. "Genomic Fabrics of the Excretory System’s Functional Pathways Remodeled in Clear Cell Renal Cell Carcinoma." Current Issues in Molecular Biology 45, no. 12 (November 24, 2023): 9471–99. http://dx.doi.org/10.3390/cimb45120594.

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Clear cell renal cell carcinoma (ccRCC) is the most frequent form of kidney cancer. Metastatic stages of ccRCC reduce the five-year survival rate to 15%. In this report, we analyze the ccRCC-induced remodeling of the five KEGG-constructed excretory functional pathways in a surgically removed right kidney and its metastasis in the chest wall from the perspective of the Genomic Fabric Paradigm (GFP). The GFP characterizes every single gene in each region by these independent variables: the average expression level (AVE), relative expression variability (REV), and expression correlation (COR) with each other gene. While the traditional approach is limited to only AVE analysis, the novel REV analysis identifies the genes whose correct expression level is critical for cell survival and proliferation. The COR analysis determines the real gene networks responsible for functional pathways. The analyses covered the pathways for aldosterone-regulated sodium reabsorption, collecting duct acid secretion, endocrine and other factor-regulated sodium reabsorption, proximal tubule bicarbonate reclamation, and vasopressin-regulated water reabsorption. The present study confirms the conclusion of our previously published articles on prostate and kidney cancers that even equally graded cancer nodules from the same tumor have different transcriptomic topologies. Therefore, the personalization of anti-cancer therapy should go beyond the individual, to his/her major cancer nodules.

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Journal articles on the topic 'Remodelled genes'

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