Journal articles: 'Bivalent chromatin'

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Grandy, Rodrigo A., Troy W. Whitfield, Hai Wu, Mark P. Fitzgerald, Jennifer J. VanOudenhove, Sayyed K. Zaidi, Martin A. Montecino, et al. "Genome-Wide Studies Reveal that H3K4me3 Modification in Bivalent Genes Is Dynamically Regulated during the Pluripotent Cell Cycle and Stabilized upon Differentiation." Molecular and Cellular Biology 36, no. 4 (December 7, 2015): 615–27. http://dx.doi.org/10.1128/mcb.00877-15.

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Stem cell phenotypes are reflected by posttranslational histone modifications, and this chromatin-related memory must be mitotically inherited to maintain cell identity through proliferative expansion. In human embryonic stem cells (hESCs), bivalent genes with both activating (H3K4me3) and repressive (H3K27me3) histone modifications are essential to sustain pluripotency. Yet, the molecular mechanisms by which this epigenetic landscape is transferred to progeny cells remain to be established. By mapping genomic enrichment of H3K4me3/H3K27me3 in pure populations of hESCs in G2, mitotic, and G1phases of the cell cycle, we found striking variations in the levels of H3K4me3 through the G2-M-G1transition. Analysis of a representative set of bivalent genes revealed that chromatin modifiers involved in H3K4 methylation/demethylation are recruited to bivalent gene promoters in a cell cycle-dependent fashion. Interestingly, bivalent genes enriched with H3K4me3 exclusively during mitosis undergo the strongest upregulation after induction of differentiation. Furthermore, the histone modification signature of genes that remain bivalent in differentiated cells resolves into a cell cycle-independent pattern after lineage commitment. These results establish a new dimension of chromatin regulation important in the maintenance of pluripotency.

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Boehm, E. W. A., and D. J. McLaughlin. "An ultrastructural karyotype for the fungus Eocronartium muscicola using epifluorescence preselection of pachytene nuclei." Canadian Journal of Botany 69, no. 6 (June 1, 1991): 1309–20. http://dx.doi.org/10.1139/b91-170.

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Mithramycin-stained nuclei in midpachynema of prophase I were preselected with epifluorescence microscopy as judged by their degree of chomatin condensation. The pachytene nuclei were processed for transmission electron microscopy (TEM) to generate ultrastructural karyotypes for Eocronartium muscicola (Fr.) Fitz. using three-dimensional reconstructions from serial sections of synaptonemal complexes. This is the first report of the use of epifluorescence to preselect fungal pachytene nuclei prior to serial sectioning for TEM and the first ultrastructural karyotype for a heterobasidiomycete. Preselection helped ensure that nuclei were in comparable states of chromatin condensation and influenced the accuracy of cross-correlating bivalent length measurements. Seventeen synapsed homologues were resolved in each of six fully reconstructed pachytene nuclei, originating from two different moss hosts, and four yielded comparable total genomic length measurements. Six of the 17 bivalents were cross-correlated among the four nuclei based on calculated length and centromeric index: the shortest and longest most extreme metacentric and submetacentric bivalents, and the bivalent associated with the nucleolus and the spindle pole body (SPB). The SPB-associated bivalent may relate to the heterochromatin found to subtend the SPB in nonpachytene stages. Key words: chromosomes, Eocronartium, epifluorescence, heterobasidiomycete, karyotype, pachynema, synaptonemal complex, spindle pole body, ultrastructure, Uredinales.

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TIKOO, Kulbhushan, Sunita GUPTA, Q. Anwar HAMID, Vanya SHAH, Bishwanath CHATTERJEE, and Ziledar ALI. "Structure of active chromatin: isolation and characterization of transcriptionally active chromatin from rat liver." Biochemical Journal 322, no. 1 (February 15, 1997): 273–79. http://dx.doi.org/10.1042/bj3220273.

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Rat liver nuclei were isolated in low-ionic-strength buffer in the absence of bi- and multi-valent cations. Digestion of these nuclei by endogenous nuclease, micrococcal nuclease and DNase I revealed that a minor chromatin fraction was preferentially digested into poly- and oligo-nucleosomes. Southern blot hybridization with various active gene probes confirmed that these chromatin fragments represent coding and 5ƀ upstream regions of transcriptionally active chromatin. Active chromatin fragments were released selectively into the medium, with inactive chromatin remaining inside the nuclei, under the above ionic conditions. The inclusion of bivalent cations during the digestion of nuclei reversed the solubility behaviour of active chromatin. Rearrangement and exchange of histone H1 between chromatin fragments was prevented by using low-salt conditions in all steps in the absence of bivalent cations. All histones, including H1, were present in stoichiometric amounts in this active chromatin fraction. Active nucleosomes showed a lower electrophoretic mobility than bulk nucleosomes in an acrylamide/agarose composite gel in the absence of Mg2+, but were selectively bound to the gel in the presence of this ion.

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Markouli, Mariam, Dimitrios Strepkos, Kostas A. Papavassiliou, Athanasios G. Papavassiliou, and Christina Piperi. "Bivalent Genes Targeting of Glioma Heterogeneity and Plasticity." International Journal of Molecular Sciences 22, no. 2 (January 7, 2021): 540. http://dx.doi.org/10.3390/ijms22020540.

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Gliomas account for most primary Central Nervous System (CNS) neoplasms, characterized by high aggressiveness and low survival rates. Despite the immense research efforts, there is a small improvement in glioma survival rates, mostly attributed to their heterogeneity and complex pathophysiology. Recent data indicate the delicate interplay of genetic and epigenetic mechanisms in regulating gene expression and cell differentiation, pointing towards the pivotal role of bivalent genes. Bivalency refers to a property of chromatin to acquire more than one histone marks during the cell cycle and rapidly transition gene expression from an active to a suppressed transcriptional state. Although first identified in embryonal stem cells, bivalent genes have now been associated with tumorigenesis and cancer progression. Emerging evidence indicates the implication of bivalent gene regulation in glioma heterogeneity and plasticity, mainly involving Homeobox genes, Wingless-Type MMTV Integration Site Family Members, Hedgehog protein, and Solute Carrier Family members. These genes control a wide variety of cellular functions, including cellular differentiation during early organism development, regulation of cell growth, invasion, migration, angiogenesis, therapy resistance, and apoptosis. In this review, we discuss the implication of bivalent genes in glioma pathogenesis and their potential therapeutic targeting options.

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Markouli, Mariam, Dimitrios Strepkos, Kostas A. Papavassiliou, Athanasios G. Papavassiliou, and Christina Piperi. "Bivalent Genes Targeting of Glioma Heterogeneity and Plasticity." International Journal of Molecular Sciences 22, no. 2 (January 7, 2021): 540. http://dx.doi.org/10.3390/ijms22020540.

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Gliomas account for most primary Central Nervous System (CNS) neoplasms, characterized by high aggressiveness and low survival rates. Despite the immense research efforts, there is a small improvement in glioma survival rates, mostly attributed to their heterogeneity and complex pathophysiology. Recent data indicate the delicate interplay of genetic and epigenetic mechanisms in regulating gene expression and cell differentiation, pointing towards the pivotal role of bivalent genes. Bivalency refers to a property of chromatin to acquire more than one histone marks during the cell cycle and rapidly transition gene expression from an active to a suppressed transcriptional state. Although first identified in embryonal stem cells, bivalent genes have now been associated with tumorigenesis and cancer progression. Emerging evidence indicates the implication of bivalent gene regulation in glioma heterogeneity and plasticity, mainly involving Homeobox genes, Wingless-Type MMTV Integration Site Family Members, Hedgehog protein, and Solute Carrier Family members. These genes control a wide variety of cellular functions, including cellular differentiation during early organism development, regulation of cell growth, invasion, migration, angiogenesis, therapy resistance, and apoptosis. In this review, we discuss the implication of bivalent genes in glioma pathogenesis and their potential therapeutic targeting options.

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King, J., L. A. Roberts, M. J. Kearsey, H. M. Thomas, R. N. Jones, L. Huang, I. P. Armstead, W. G. Morgan, and I. P. King. "A Demonstration of a 1:1 Correspondence Between Chiasma Frequency and Recombination Using a Lolium perenne/Festuca pratensis Substitution." Genetics 161, no. 1 (May 1, 2002): 307–14. http://dx.doi.org/10.1093/genetics/161.1.307.

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Abstract A single chromosome of the grass species Festuca pratensis has been introgressed into Lolium perenne to produce a diploid monosomic substitution line (2n = 2x = 14). The chromatin of F. pratensis and L. perenne can be distinguished by genomic in situ hybridization (GISH), and it is therefore possible to visualize the substituted F. pratensis chromosome in the L. perenne background and to study chiasma formation in a single marked bivalent. Recombination occurs freely in the F. pratensis/L. perenne bivalent, and chiasma frequency counts give a predicted map length for this bivalent of 76 cM. The substituted F. pratensis chromosome was also mapped with 104 EcoRI/Tru91 and HindIII/Tru91 amplified fragment length polymorphisms (AFLPs), generating a marker map of 81 cM. This map length is almost identical to the map length of 76 cM predicted from the chiasma frequency data. The work demonstrates a 1:1 correspondence between chiasma frequency and recombination and, in addition, the absence of chromatid interference across the Festuca and Lolium centromeres.

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Weishaupt, Holger, Mikael Sigvardsson, and Joanne L. Attema. "Epigenetic chromatin states uniquely define the developmental plasticity of murine hematopoietic stem cells." Blood 115, no. 2 (January 14, 2010): 247–56. http://dx.doi.org/10.1182/blood-2009-07-235176.

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Abstract Heritable epigenetic signatures are proposed to serve as an important regulatory mechanism in lineage fate determination. To investigate this, we profiled chromatin modifications in murine hematopoietic stem cells, lineage-restricted progenitors, and CD4+ T cells using modified genome-scale mini-chromatin immunoprecipitation technology. We show that genes involved in mature hematopoietic cell function associate with distinct chromatin states in stem and progenitor cells, before their activation or silencing upon cellular maturation. Many lineage-restricted promoters are associated with bivalent histone methylation and highly combinatorial histone modification patterns, which may determine their selective priming of gene expression during lineage commitment. These bivalent chromatin states are conserved in mammalian evolution, with a particular overrepresentation of promoters encoding key regulators of hematopoiesis. After differentiation into progenitors and T cells, activating histone modifications persist at transcriptionally repressed promoters, suggesting that these transcriptional programs might be reactivated after lineage restriction. Collectively, our data reveal the epigenetic framework that underlies the cell fate options of hematopoietic stem cells.

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Yu, Hongyao, Jiajia Wang, Brad Lackford, Brian Bennett, Jian-liang Li, and Guang Hu. "INO80 promotes H2A.Z occupancy to regulate cell fate transition in pluripotent stem cells." Nucleic Acids Research 49, no. 12 (June 17, 2021): 6739–55. http://dx.doi.org/10.1093/nar/gkab476.

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Abstract The INO80 chromatin remodeler is involved in many chromatin-dependent cellular functions. However, its role in pluripotency and cell fate transition is not fully defined. We examined the impact of Ino80 deletion in the naïve and primed pluripotent stem cells. We found that Ino80 deletion had minimal effect on self-renewal and gene expression in the naïve state, but led to cellular differentiation and de-repression of developmental genes in the transition toward and maintenance of the primed state. In the naïve state, INO80 pre-marked gene promoters that would adopt bivalent histone modifications by H3K4me3 and H3K27me3 upon transition into the primed state. In the primed state, in contrast to its known role in H2A.Z exchange, INO80 promoted H2A.Z occupancy at these bivalent promoters and facilitated H3K27me3 installation and maintenance as well as downstream gene repression. Together, our results identified an unexpected function of INO80 in H2A.Z deposition and gene regulation. We showed that INO80-dependent H2A.Z occupancy is a critical licensing step for the bivalent domains, and thereby uncovered an epigenetic mechanism by which chromatin remodeling, histone variant deposition and histone modification coordinately control cell fate.

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De Gobbi, Marco, David Garrick, Magnus Lynch, Douglas Vernimmen, Jim R. Hughes, Nicolas Goardon, Sidinh Luc, et al. "Generation of bivalent chromatin domains during cell fate decisions." Epigenetics & Chromatin 4, no. 1 (2011): 9. http://dx.doi.org/10.1186/1756-8935-4-9.

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10

Yang, X. William. "Life and death rest on a bivalent chromatin state." Nature Neuroscience 19, no. 10 (September 27, 2016): 1271–73. http://dx.doi.org/10.1038/nn.4396.

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11

Olins, Donald E., and Ada L. Olins. "Epichromatin and chromomeres: a ‘fuzzy’ perspective." Open Biology 8, no. 6 (June 2018): 180058. http://dx.doi.org/10.1098/rsob.180058.

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‘Epichromatin’, the surface of chromatin beneath the interphase nuclear envelope (NE) or at the surface of mitotic chromosomes, was discovered by immunostaining with a specific bivalent mouse monoclonal anti-nucleosome antibody (mAb PL2-6). ‘Chromomeres’, punctate chromatin particles approximately 200–300 nm in diameter, identified throughout the interphase chromatin and along mitotic chromosomes, were observed by immunostaining with the monovalent papain-derived Fab fragments of bivalent PL2-6. The specific target for PL2-6 appears to include the nucleosome acidic patch. Thus, within the epichromatin and chromomeric regions, this epitope is ‘exposed’. Considering that histones possess unstructured ‘tails’ (i.e. intrinsically disordered peptide regions, IDPR), our perception of these chromatin regions becomes more ‘fuzzy’ (less defined). We suggest that epichromatin cationic tails facilitate interactions with anionic components of NE membranes. We also suggest that the unstructured histone tails (especially, histone H1 tails), with their presumed promiscuous binding, establish multivalent binding that stabilizes each chromomere as a unit of chromatin higher order structure. We propose an ‘unstructured stability’ hypothesis, which postulates that the stability of epichromatin and chromomeres (as well as other nuclear chromatin structures) is a consequence of the collective contributions of numerous weak histone IDPR binding interactions arising from the multivalent nucleosome, analogous to antibody avidity.

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Huang, Rongsheng, and Jinzhi Lei. "Dynamics of gene expression with positive feedback to histone modifications at bivalent domains." International Journal of Modern Physics B 32, no. 07 (March 5, 2018): 1850075. http://dx.doi.org/10.1142/s0217979218500753.

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Experiments have shown that in embryonic stem cells, the promoters of many lineage-control genes contain “bivalent domains”, within which the nucleosomes possess both active (H3K4me3) and repressive (H3K27me3) marks. Such bivalent modifications play important roles in maintaining pluripotency in embryonic stem cells. Here, to investigate gene expression dynamics when there are regulations in bivalent histone modifications and random partition in cell divisions, we study how positive feedback to histone methylation/demethylation controls the transition dynamics of the histone modification patterns along with cell cycles. We constructed a computational model that includes dynamics of histone marks, three-stage chromatin state transitions, transcription and translation, feedbacks from protein product to enzymes to regulate the addition and removal of histone marks, and the inheritance of nucleosome state between cell cycles. The model reveals how dynamics of both nucleosome state transition and gene expression are dependent on the enzyme activities and feedback regulations. Results show that the combination of stochastic histone modification at each cell division and the deterministic feedback regulation work together to adjust the dynamics of chromatin state transition in stem cell regenerations.

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Gao, Yuan, Haiyun Gan, Zhenkun Lou, and Zhiguo Zhang. "Asf1a resolves bivalent chromatin domains for the induction of lineage-specific genes during mouse embryonic stem cell differentiation." Proceedings of the National Academy of Sciences 115, no. 27 (June 18, 2018): E6162—E6171. http://dx.doi.org/10.1073/pnas.1801909115.

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Bivalent chromatin domains containing repressive H3K27me3 and active H3K4me3 modifications are barriers for the expression of lineage-specific genes in ES cells and must be resolved for the transcription induction of these genes during differentiation, a process that remains largely unknown. Here, we show that Asf1a, a histone chaperone involved in nucleosome assembly and disassembly, regulates the resolution of bivalent domains and activation of lineage-specific genes during mouse ES cell differentiation. Deletion of Asf1a does not affect the silencing of pluripotent genes, but compromises the expression of lineage-specific genes during ES cell differentiation. Mechanistically, the Asf1a–histone interaction, but not the role of Asf1a in nucleosome assembly, is required for gene transcription. Asf1a is recruited to several bivalent promoters, partially through association with transcription factors, and mediates nucleosome disassembly during differentiation. We suggest that Asf1a-mediated nucleosome disassembly provides a means for resolution of bivalent domain barriers for induction of lineage-specific genes during differentiation.

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Cheng, Jason X., John Anastasi, and James W. Vardiman. "Disease-Associated Chromatin Conformation and Therapeutic Implications In Leukemia." Blood 122, no. 21 (November 15, 2013): 4892. http://dx.doi.org/10.1182/blood.v122.21.4892.4892.

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Disease- or treatment-associated chromatin conformation has yet to be illustrated. Here we first demonstrate that monocytic and erythroid leukemia cell lines have distinctly different chromatin conformation at the PU.1 locus: a looped, connected, RNA-polymerase-II-bound, active conformation in the former and a disconnected, inactive conformation in the latter. These conformations undergo opposite transformations, becoming more active in the erythroid leukemia line and less active in the monocytic leukemia line, in response to both DNA and histone hypomethylating drugs.To explore the underlying mechanisms we developed a novel method to analyze DNA modifications. We demonstrate that the erythroid leukemia line has a marked drug-responsive change in both hydroxymethyl-CpG and 5-meythyl-CpG at the promoter, whereas the monocytic leukemia line has a higher level bivalent histone/chromatin with co-localized H3K4me3 and H3K27me3 at the enhancer. Consequently, the erythroid leukemia line is more sensitive to DNA hypomethylation while the monocytic leukemia line is more sensitive to histone hypomethylation. Further studies on clinical leukemia samples confirm the findings, and demonstrate that the leukemic cells from the clinical samples have different chromatin conformations with much more bivalent chromatin and denser DNA/histone modifiers and are more sensitive to hypomethylating drugs, compared to normal controls. Different chromatin conformations dictate preferential drug responses and open new diagnostic and therapeutic avenues. Disclosures: No relevant conflicts of interest to declare.

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Harikumar, Arigela, and Eran Meshorer. "Chromatin remodeling and bivalent histone modifications in embryonic stem cells." EMBO reports 16, no. 12 (November 9, 2015): 1609–19. http://dx.doi.org/10.15252/embr.201541011.

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Diehl, Katharine L., Eva J. Ge, Daniel N. Weinberg, Krupa S. Jani, C. David Allis, and Tom W. Muir. "PRC2 engages a bivalent H3K27M-H3K27me3 dinucleosome inhibitor." Proceedings of the National Academy of Sciences 116, no. 44 (October 14, 2019): 22152–57. http://dx.doi.org/10.1073/pnas.1911775116.

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A lysine-to-methionine mutation at lysine 27 of histone 3 (H3K27M) has been shown to promote oncogenesis in a subset of pediatric gliomas. While there is evidence that this “oncohistone” mutation acts by inhibiting the histone methyltransferase PRC2, the details of this proposed mechanism nevertheless continue to be debated. Recent evidence suggests that PRC2 must simultaneously bind both H3K27M and H3K27me3 to experience competitive inhibition of its methyltransferase activity. In this work, we used PRC2 inhibitor treatments in a transgenic H3K27M cell line to validate this dependence in a cellular context. We further used designer chromatin inhibitors to probe the geometric constraints of PRC2 engagement of H3K27M and H3K27me3 in a biochemical setting. We found that PRC2 binds to a bivalent inhibitor unit consisting of an H3K27M and an H3K27me3 nucleosome and exhibits a distance dependence in its affinity for such an inhibitor, which favors closer proximity of the 2 nucleosomes within a chromatin array. Together, our data precisely delineate fundamental aspects of the H3K27M inhibitor and support a model wherein PRC2 becomes trapped at H3K27M-H3K27me3 boundaries.

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Fuková, Iva, Petr Nguyen, and Frantiek Marec. "Codling moth cytogenetics: karyotype, chromosomal location of rDNA, and molecular differentiation of sex chromosomes." Genome 48, no. 6 (December 1, 2005): 1083–92. http://dx.doi.org/10.1139/g05-063.

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We performed a detailed karyotype analysis in the codling moth, Cydia pomonella (L.) (Lepidoptera: Tortricidae), the key pest of pome fruit in the temperate regions of the world. The codling moth karyotype consisted of 2n = 56 chromosomes of a holokinetic type. The chromosomes were classified into 5 groups according to their sizes: extra large (3 pairs), large (3 pairs), medium (15 pairs), small (5 pairs), and dot-like (2 pairs). In pachytene nuclei of both sexes, a curious NOR (nucleolar organizer region) bivalent was observed. It carried 2 nucleoli, each associated with one end of the bivalent. FISH with an 18S ribosomal DNA probe confirmed the presence of 2 clusters of rRNA genes at the opposite ends of the bivalent. In accordance with this finding, 2 homologous NOR chromosomes were identified in mitotic metaphase, each showing hybridization signals at both ends. In highly polyploid somatic nuclei, females showed a large heterochromatin body, the so-called sex chromatin or W chromatin. The heterochromatin body was absent in male nuclei, indicating a WZ/ZZ (female/male) sex chromosome system. In keeping with the sex chromatin status, pachytene oocytes showed a sex chromosome bivalent (WZ) that was easily discernible by its heterochromatic W thread. To study molecular differentiation of the sex chromosomes, we employed genomic in situ hybridization (GISH) and comparative genomic hybridization (CGH). GISH detected the W chromosome by strong binding of the Cy3-labelled, female-derived DNA probe. With CGH, both the Cy3-labelled female-derived probe and Fluor-X labelled male-derived probe evenly bound to the W chromosome. This suggested that the W chromosome is predominantly composed of repetitive DNA sequences occurring scattered in other chromosomes but accumulated in the W chromosome. The demonstrated ways of W chromosome identification will facilitate the development of genetic sexing strains desirable for pest control using the sterile insect technique.Key words: CGH, codling moth, FISH, GISH, genomic hybridization, heterochromatin, holokinetic chromosomes, karyotype, NOR, rDNA, SIT, sex chromosomes.

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Rakyan, V. K., T. A. Down, S. Maslau, T. Andrew, T. P. Yang, H. Beyan, P. Whittaker, et al. "Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains." Genome Research 20, no. 4 (March 10, 2010): 434–39. http://dx.doi.org/10.1101/gr.103101.109.

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Mazzarella, Luca, Helle F. Jørgensen, Jorge Soza-Ried, Anna V. Terry, Stella Pearson, Georges Lacaud, Valerie Kouskoff, Matthias Merkenschlager, and Amanda G. Fisher. "Embryonic stem cell–derived hemangioblasts remain epigenetically plastic and require PRC1 to prevent neural gene expression." Blood 117, no. 1 (January 6, 2011): 83–87. http://dx.doi.org/10.1182/blood-2010-03-273128.

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Abstract Many lineage-specific developmental regulator genes are transcriptionally primed in embryonic stem (ES) cells; RNA PolII is bound at their promoters but is prevented from productive elongation by the activity of polycomb repressive complexes (PRC) 1 and 2. This epigenetically poised state is thought to enable ES cells to rapidly execute multiple differentiation programs and is recognized by a simultaneous enrichment for trimethylation of lysine 4 and trimethylation of lysine 27 of histone H3 (bivalent chromatin) across promoter regions. Here we show that the chromatin profile of this important cohort of genes is progressively modified as ES cells differentiate toward blood-forming precursors. Surprisingly however, neural specifying genes, such as Nkx2-2, Nkx2-9, and Sox1, remain bivalent and primed even in committed hemangioblasts, as conditional deletion of PRC1 results in overt and inappropriate expression of neural genes in hemangioblasts. These data reinforce the importance of PRC1 for normal hematopoietic differentiation and reveal an unexpected epigenetic plasticity of mesoderm-committed hemangioblasts.

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Albini, S. M., and T. Schwarzacher. "In situ localization of two repetitive DNA sequences to surface-spread pachytene chromosomes of rye." Genome 35, no. 4 (August 1, 1992): 551–59. http://dx.doi.org/10.1139/g92-082.

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Surface-spread pollen mother cells at meiotic prophase from Secale cereale (rye) were used for fluorescent DNA:DNA in situ localization of two tandemly repeated DNA sequences: pTa71, a wheat rDNA clone, and pSc119.2, a cloned 120-bp repeat from rye heterochromatin. The fluorescent hybridization signal, consisting of many yellow-green dots, was closely associated with the bivalent axes, corresponding to the synaptonemal complex, and located in the surrounding chromatin. The rDNA signal was associated with one bivalent, the smallest of the seven, at a distance about 13% of the bivalent length from the telomere. This corresponded to the position of the nucleolar organizing region of silver-stained synaptonemal complexes analyzed under the electron microscope and published data for somatic metaphase chromosomes. The relative length of the axis covered with the rDNA signal is less than expected from somatic metaphases, but it corresponds more closely to the proportion of the sequences in the genome. The hybridization signal with the 120-bp repeat was located mainly at the telomeric regions of several bivalents that showed thickenings of the axis after DAPI staining, probably corresponding to somatic C-bands. These major and some minor intercalary sites agree with the distribution of the 120-bp repeat in somatic metaphase. Fluorescent in situ hybridization to plant surface-spread pachytene chromosomes, which can be obtained in large numbers, has great potential for studying meiotic prophase, high-resolution mapping of DNA sequences, and investigating the relationship of DNA sequences to the synaptonemal complex.Key words: in situ hybridization, cereals, pachytene, meiosis, synaptonemal complex, physical mapping.

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Maezawa, So, Kazuteru Hasegawa, Masashi Yukawa, Naoki Kubo, Akihiko Sakashita, Kris G. Alavattam, Ho-Su Sin, et al. "Polycomb protein SCML2 facilitates H3K27me3 to establish bivalent domains in the male germline." Proceedings of the National Academy of Sciences 115, no. 19 (April 23, 2018): 4957–62. http://dx.doi.org/10.1073/pnas.1804512115.

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Repressive H3K27me3 and active H3K4me2/3 together form bivalent chromatin domains, molecular hallmarks of developmental potential. In the male germline, these domains are thought to persist into sperm to establish totipotency in the next generation. However, it remains unknown how H3K27me3 is established on specific targets in the male germline. Here, we demonstrate that a germline-specific Polycomb protein, SCML2, binds to H3K4me2/3-rich hypomethylated promoters in undifferentiated spermatogonia to facilitate H3K27me3. Thus, SCML2 establishes bivalent domains in the male germline of mice. SCML2 regulates two major classes of bivalent domains: Class I domains are established on developmental regulator genes that are silent throughout spermatogenesis, while class II domains are established on somatic genes silenced during late spermatogenesis. We propose that SCML2-dependent H3K27me3 in the male germline prepares the expression of developmental regulator and somatic genes in embryonic development.

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Mantsoki, Anna, Karla Parussel, and Anagha Joshi. "Identification and Characterisation of Putative Enhancer Elements in Mouse Embryonic Stem Cells." Bioinformatics and Biology Insights 15 (January 2021): 117793222097462. http://dx.doi.org/10.1177/1177932220974623.

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Enhancer elements control mammalian transcription largely in a cell-type-specific manner. The genome-wide identification of enhancer elements and their activity status in a cellular context is therefore fundamental to understanding cell identity and function. We determined enhancer activity in mouse embryonic stem (ES) cells using chromatin modifications and characterised their global properties. Specifically, we first grouped enhancers into 5 groups using multiple H3K4me1, H3K27ac, and H3K27me3 modification data sets. Active enhancers (simultaneous presence of H3K4me1 and H3K27ac) were enriched for binding of pluripotency factors and were found near pluripotency-related genes. Although both H3K4me1-only and active enhancers were enriched for super-enhancers and a TATA box like motif, active enhancers were preferentially bound by RNA polII (s2) and were enriched for bidirectional transcription, while H3K4me1-only enhancers were enriched for RNA polII (8WG16) suggesting they were likely poised. Bivalent enhancers (simultaneous presence of H3K4me1 and H3K27me3) were preferentially in the vicinity of bivalent genes. They were enriched for binding of components of polycomb complex as well as Tcf3 and Oct4. Moreover, a ‘CTTTCTC’ de-novo motif was enriched at bivalent enhancers, previously identified at bivalent promoters in ES cells. Taken together, 3 histone modifications successfully demarcated active, bivalent, and poised enhancers with distinct sequence and binding features.

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Lemarié, Maud, Stefania Bottardi, Lionel Mavoungou, Helen Pak, and Eric Milot. "IKAROS is required for the measured response of NOTCH target genes upon external NOTCH signaling." PLOS Genetics 17, no. 3 (March 26, 2021): e1009478. http://dx.doi.org/10.1371/journal.pgen.1009478.

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The tumor suppressor IKAROS binds and represses multiple NOTCH target genes. For their induction upon NOTCH signaling, IKAROS is removed and replaced by NOTCH Intracellular Domain (NICD)-associated proteins. However, IKAROS remains associated to other NOTCH activated genes upon signaling and induction. Whether IKAROS could participate to the induction of this second group of NOTCH activated genes is unknown. We analyzed the combined effect of IKAROS abrogation and NOTCH signaling on the expression of NOTCH activated genes in erythroid cells. In IKAROS-deleted cells, we observed that many of these genes were either overexpressed or no longer responsive to NOTCH signaling. IKAROS is then required for the organization of bivalent chromatin and poised transcription of NOTCH activated genes belonging to either of the aforementioned groups. Furthermore, we show that IKAROS-dependent poised organization of the NOTCH target Cdkn1a is also required for its adequate induction upon genotoxic insults. These results highlight the critical role played by IKAROS in establishing bivalent chromatin and transcriptional poised state at target genes for their activation by NOTCH or other stress signals.

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Hezroni, Hadas, Badi Sri Sailaja, and Eran Meshorer. "Pluripotency-related, Valproic Acid (VPA)-induced Genome-wide Histone H3 Lysine 9 (H3K9) Acetylation Patterns in Embryonic Stem Cells." Journal of Biological Chemistry 286, no. 41 (August 17, 2011): 35977–88. http://dx.doi.org/10.1074/jbc.m111.266254.

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Embryonic stem cell (ESC) chromatin is characterized by a unique set of histone modifications, including enrichment for H3 lysine 9 acetylation (H3K9ac). Recent studies suggest that histone deacetylase (HDAC) inhibitors promote pluripotency. Here, using H3K9ac ChIP followed by high throughput sequencing analyses and gene expression in E14 mouse ESCs before and after treatment with a low level of the HDAC inhibitor valproic acid, we show that H3K9ac is enriched at gene promoters and is highly correlated with gene expression and with various genomic features, including different active histone marks and pluripotency-related transcription factors. Curiously, it predicts the cellular location of gene products. Treatment of ESCs with valproic acid leads to a pervasive genome-wide and time-dependent increase in H3K9ac, but this increase is selectively suppressed after 4 h in H3K4me3/H3K27me3 bivalent genes. H3K9ac increase is dependent on the promoter's chromatin state and is affected by the binding of P300, various transcription factors, and active histone marks. This study provides insights into the genomic response of ESCs to a low level of HDAC inhibitor, which leads to increased pluripotency. The results suggest that a mild (averaging less than 40%) but global change in the chromatin state is involved in increased pluripotency and that specific mechanisms operate selectively in bivalent genes to maintain constant H3K9ac levels. Our data support the notion that H3K9ac has an important role in ESC biology.

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Harker, Nicola, Anna Garefalaki, Ursula Menzel, Eleni Ktistaki, Taku Naito, Katia Georgopoulos, and Dimitris Kioussis. "Pre-TCR Signaling and CD8 Gene Bivalent Chromatin Resolution during Thymocyte Development." Journal of Immunology 186, no. 11 (April 22, 2011): 6368–77. http://dx.doi.org/10.4049/jimmunol.1003567.

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Sanz, Lionel A., Stormy Chamberlain, Jean-Charles Sabourin, Amandine Henckel, Terry Magnuson, Jean-Philippe Hugnot, Robert Feil, and Philippe Arnaud. "A mono-allelic bivalent chromatin domain controls tissue-specific imprinting at Grb10." EMBO Journal 27, no. 19 (July 24, 2008): 2523–32. http://dx.doi.org/10.1038/emboj.2008.142.

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Bernstein, Bradley E., Tarjei S. Mikkelsen, Xiaohui Xie, Michael Kamal, Dana J. Huebert, James Cuff, Ben Fry, et al. "A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells." Cell 125, no. 2 (April 2006): 315–26. http://dx.doi.org/10.1016/j.cell.2006.02.041.

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Spangenberg, Victor, Marine Arakelyan, Eduard Galoyan, Mark Pankin, Ruzanna Petrosyan, Ilona Stepanyan, Tatiana Grishaeva, Felix Danielyan, and Oxana Kolomiets. "Extraordinary centromeres: differences in the meiotic chromosomes of two rock lizards speciesDarevskia portschinskiiandDarevskia raddei." PeerJ 7 (January 30, 2019): e6360. http://dx.doi.org/10.7717/peerj.6360.

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According to the synthesis of 30 years of multidisciplinary studies, parthenogenetic species of rock lizards of genusDarevskiawere formed as a result of different combination patterns of interspecific hybridization of the four bisexual parental species:Darevskia raddei,D. mixta,D. valentini, andD. portschinskii. In particular,D. portschinskiiandD. raddeiare considered as the parental species for the parthenogenetic speciesD. rostombekowi. Here for the first time, we present the result of comparative immunocytochemical study of primary spermatocyte nuclei spreads from the leptotene to diplotene stages of meiotic prophase I in two species:D. portschinskiiandD. raddei. We observed similar chromosome lengths for both synaptonemal complex (SC) karyotypes as well as a similar number of crossing over sites. However, unexpected differences in the number and distribution of anti-centromere antibody (ACA) foci were detected in the SC structure of bivalents of the two species. In all examinedD. portschinskiispermatocyte nuclei, one immunostained centromere focus was detected per SC bivalent. In contrast, in almost every studiedD. raddeinuclei we identified three to nine SCs with additional immunostained ACA foci per SC bivalent. Thus, the obtained results allow us to identify species-specific karyotype features, previously not been detected using conventional mitotic chromosome analysis. Presumably the additional centromere foci are result of epigenetic chromatin modifications. We assume that this characteristic of theD. raddeikaryotype could represent useful marker for the future studies of parthenogenetic species hybrid karyotypes related toD. raddei.

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Béguelin, Wendy, Matt R. Teater, Katerina Hatzi, Relja Popovich, Yanwen Jiang, Karen L. Bunting, Monica Rosen, et al. "EZH2 and BCL6 Cooperate To Create The Germinal Center B-Cell Phenotype and Induce Lymphomas Through Formation and Repression Of Bivalent Chromatin Domains." Blood 122, no. 21 (November 15, 2013): 1. http://dx.doi.org/10.1182/blood.v122.21.1.1.

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Abstract The EZH2 histone methyltransferase is the enzymatic core of the Polycomb repressor 2 (PRC2 complex), is highly upregulated in germinal center (GC) B cells and is targeted by gain-of-function somatic mutations that enhance its ability to trimethylate histone 3 lysine 27 in diffuse large B cell lymphomas (DLBCLs) and follicular lymphomas (FLs). We explored the significance and mechanism of action of EZH2 in normal GC development and lymphomagenesis. We observed that EZH2-conditional knockout mice and mice exposed to the novel EZH2-specific inhibitor GSK503 both completely failed to form GCs or high affinity antibodies. Using ChIP-seq, sequential QChIP, RNA-seq and functional assays we demonstrated that EZH2 mediates the GC phenotype through de novo formation of bivalently marked chromatin domains (characterized by overlapping H3K27me3 repressive mark with the H3K4me3 activation mark) at the promoters of target genes involved in cell cycle regulation (e.g. CDKN1A) and in GC exit and terminal differentiation program (e.g. IRF4 and PRDM1). Notably, mutant EZH2 caused hyper-repression of these bivalent genes through increased H3K27me3, which we showed is causal to the mutant EZH2 phenotype. Mice engineered to conditionally express lymphoma-associated EZH2Y641F exhibited aberrant suppression of bivalent gene expression leading to increased proliferation, blockade of terminal differentiation, and massive GC hyperplasia. Transcriptional profiles of human DLBCL patients revealed that those with mutant EZH2 display a unique signature consisting of silencing of GC bivalent genes, suggesting that mutant EZH2 contributes to human lymphomagenesis through paralysis of bivalent chromatin domains. This scenario is reminiscent of the role of the transcriptional repressor BCL6, which is also required for GC formation. BCL6 also represses CDKN1A, IRF4 and PRDM1 and is required to maintain the proliferation and survival of DLBCL cells. Notably BCL6 represses its targets by associating with BCoR, which forms a variant of Polycomb repressor 1 (PRC1) complex. We hypothesized that EZH2 and BCL6 cooperate to mediate the GC B-cell phenotype and when aberrantly active may cooperate to form GC-derived B-cell lymphomas. Using ChIP-seq studies we found that the target promoters of BCL6-BCoR complex (but not promoters with BCL6 complexes lacking BCoR) significantly overlap with EZH2 bivalent promoter genes in primary human GC B cells and lymphoma cells (Hypergeometric test, p=1.5x10-26). Treatment of DLBCL cells with EZH2 or BCL6 inhibitors or siRNA partially derepressed these genes indicating that both factors cooperate and are required to mediate full repression of these crucial loci. To determine whether EZH2 and BCL6 cooperate to generate GC-derived lymphomas, we transduced bone marrow of IµHABCL6 mice (which mimic BCL6 translocations in DLBCL) with retrovirus encoding mutant EZH2Y641F or GFP alone, and transplanted them into lethally irradiated recipients. Only EZH2Y641F/BCL6 mice showed an accelerated lethal phenotype (log-rank test, p=0.007), with reduced median survival (EZH2Y641F: 309 days, empty vector: 453 days). Serial bone marrow transplantation resulted in even further increased lethality (log-rank test, p=0.004; median survival EZH2Y641F: 127 days, empty vector: 169 days). Given the oncogenic cooperation between BCL6 and EZH2, we hypothesized that rational combinatorial therapy with BCL6 and EZH2 inhibitors might synergistically kill DLBCLs. Indeed, by combining the EZH2 inhibitor GSK343 and the RI-BPI, a drug that inhibits BCL6 by abrogating its interaction with BCoR, we observed a potent synergistic effect on the inhibition of DLBCL cell lines proliferation. The combination of these two inhibitors in mice bearing DLBCL xenografts accordingly suppressed tumor growth more effectively than either agent alone. Finally, the combination also yielded further killing of primary human DLBCL cells growth in a co-culture system that we developed for testing primary human specimens. In summary we identified the first epigenetic mechanism of lymphomagenesis involving aberrant repression of GC-specific bivalent domains by EZH2 (PRC2) in cooperation with BCL6-BCoR (PRC1) complexes, as well as a rational epigenetic-based and molecular targeted therapeutic approach with the potential to eradicate lymphomas without harming normal tissues. Disclosures: Creasy: GlaxoSmithKline: Employment.

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Beumer, Kelly J., Sergio Pimpinelli, and Kent G. Golic. "Induced Chromosomal Exchange Directs the Segregation of Recombinant Chromatids in Mitosis of Drosophila." Genetics 150, no. 1 (September 1, 1998): 173–88. http://dx.doi.org/10.1093/genetics/150.1.173.

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Abstract In meiosis, the segregation of chromosomes at the reductional division is accomplished by first linking homologs together. Genetic exchange generates the bivalents that direct regular chromosome segregation. We show that genetic exchange in mitosis also generates bivalents and that these bivalents direct mitotic chromosome segregation. After FLP-mediated homologous recombination in G2 of the cell cycle, recombinant chromatids consistently segregate away from each other (x segregation). This pattern of segregation also applies to exchange between heterologs. Most, or all, cases of non-x segregation are the result of exchange in G1. Cytological evidence is presented that confirms the existence of the bivalents that direct this pattern of segregation. Our results implicate sister chromatid cohesion in maintenance of the bivalent. The pattern of chromatid segregation can be altered by providing an additional FRT at a more proximal site on one chromosome. We propose that sister chromatid exchange occurs at the more proximal site, allowing the recombinant chromatids to segregate together. This also allowed the recovery of reciprocal translocations following FLP-mediated heterologous recombination. The observation that exchange can generate a bivalent in mitotic divisions provides support for a simple evolutionary relationship between mitosis and meiosis.

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Lee, Sun-Min, Jungwoo Lee, Kyung-Min Noh, Won-Young Choi, Sejin Jeon, Goo Taeg Oh, Jeongsil Kim-Ha, Yoonhee Jin, Seung-Woo Cho, and Young-Joon Kim. "Intragenic CpG islands play important roles in bivalent chromatin assembly of developmental genes." Proceedings of the National Academy of Sciences 114, no. 10 (February 21, 2017): E1885—E1894. http://dx.doi.org/10.1073/pnas.1613300114.

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CpG, 5′-C-phosphate-G-3′, islands (CGIs) have long been known for their association with enhancers, silencers, and promoters, and for their epigenetic signatures. They are maintained in embryonic stem cells (ESCs) in a poised but inactive state via the formation of bivalent chromatin containing both active and repressive marks. CGIs also occur within coding sequences, where their functional role has remained obscure. Intragenic CGIs (iCGIs) are largely absent from housekeeping genes, but they are found in all genes associated with organ development and cell lineage control. In this paper, we investigated the epigenetic status of iCGIs and found that they too reside in bivalent chromatin in ESCs. Cell type-specific DNA methylation of iCGIs in differentiated cells was linked to the loss of both the H3K4me3 and H3K27me3 marks, and disruption of physical interaction with promoter regions, resulting in transcriptional activation of key regulators of differentiation such as PAXs, HOXs, and WNTs. The differential epigenetic modification of iCGIs appears to be mediated by cell type-specific transcription factors distinct from those bound by promoter, and these transcription factors may be involved in the hypermethylation of iCGIs upon cell differentiation. iCGIs thus play a key role in the cell type-specific regulation of transcription.

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Ford, Rhodes, Paolo Vignali, Natalie Rittenhouse, Nicole Scharping, Andrew Frisch, Greg Delgoffe, and Amanda Poholek. "518 Epigenetic dysfunction of terminally exhausted tumor infiltrating T cells." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A554. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0518.

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BackgroundTumor-infiltrating CD8+ T cells have been characterized by their exhausted phenotype with decreased cytokine expression and increased expression of co-inhibitory receptors, such as PD-1 and Tim-3. These receptors mark the progression towards exhaustion from a progenitor stage (PD-1Low) to a terminally exhausted stage (PD-1+Tim-3+). While the epigenetics of tumor-infiltrating T cells are unique compared to naïve, effector, and memory populations, how the chromatin landscape changes during this progression has not been described.MethodsUsing a low-input ChIP-based assay called Cleavage Under Targets and Release Using Nuclease (CUT&RUN), we profiled the histone modifications at the chromatin of tumor-infiltrating CD8+ T cell subsets to better understand the relationship between the epigenome and the transcriptome as TIL progress towards terminal exhaustion.ResultsWe have identified two epigenetic characteristics unique to terminally exhausted cells. First, we found a substantial increase in the number of genes that exhibit bivalent chromatin marks, defined by the presence of both activating (H3K4me3) and repressive (H3K27me3) epigenetic modifications that inhibit gene expression. In contrast to stem cells which exhibit bivalency, bivalent genes in terminally exhausted T cells are not associated with plasticity and represent aberrant hypermethylation in response to tumor hypoxia. Secondly, we have also identified a unique set of enhancers, characterized by H3K27ac that do not drive gene expression. These enhancers are enriched for AP-1 transcription factors, whereas enhancers that correlate with gene transcription are enriched for nuclear receptor (NR) transcription factors. Intriguingly, while most AP-1 and NR transcription factors are not expressed in terminally exhausted cells, we found that Batf, an inhibitory AP-1 family member, and Nr4a2, a NR known to promote both exhaustion and modify chromatin were specifically expressed in terminally exhausted cells. These data suggest the balance of Batf and Nr4a2 may modulate the enhancer landscape to promote terminal exhaustion, while hypoxia simultaneously promotes hypermethylation and gene repression.ConclusionsOur study defines for the first time the features of epigenetic dysfunction in tumor-mediated T cell exhaustion and deepens our understanding of the epigenetic regulation of gene expression. These observations are the bases for future work that will elucidate that factors that drive progression towards terminal T cell exhaustion at the epigenetic level and identify novel therapeutic targets to restore effector function of tumor T cells and mediate tumor clearance.

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Dobenecker, Marc-Werner, Jong Kyong Kim, Jonas Marcello, Terry C. Fang, Rab Prinjha, Remy Bosselut, and Alexander Tarakhovsky. "Coupling of T cell receptor specificity to natural killer T cell development by bivalent histone H3 methylation." Journal of Experimental Medicine 212, no. 3 (February 16, 2015): 297–306. http://dx.doi.org/10.1084/jem.20141499.

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The fidelity of T cell immunity depends greatly on coupling T cell receptor signaling with specific T cell effector functions. Here, we describe a chromatin-based mechanism that enables integration of TCR specificity into definite T cell lineage commitment. Using natural killer T cells (iNKT cell) as a model of a T cell subset that differentiates in response to specific TCR signaling, we identified a key role of histone H3 lysine 27 trimethylation (H3K27me3) in coupling iNKT cell TCR specificity with the generation of iNKT cells. We found that the Zbtb16/PLZF gene promoter that drives iNKT cell differentiation possesses a bivalent chromatin state characterized by the simultaneous presence of negative and positive H3K27me3 and H3K4me3 modifications. Depletion of H3K27me3 at the Zbtb16/PLZF promoter leads to uncoupling of iNKT cell development from TCR specificity and is associated with accumulation of iNKT-like CD4+ cells that express a non-iNKT cell specific T cell repertoire. In turn, stabilization of H3K27me3 leads to a drastic reduction of the iNKT cell population. Our data suggest that H3K27me3 levels at the bivalent Zbtb16/PLZF gene define a threshold enabling precise coupling of TCR specificity to lineage commitment.

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Nadarajan, Saravanapriah, Elisabeth Altendorfer, Takamune T. Saito, Marina Martinez-Garcia, and Monica P. Colaiácovo. "HIM-17 regulates the position of recombination events and GSP-1/2 localization to establish short arm identity on bivalents in meiosis." Proceedings of the National Academy of Sciences 118, no. 17 (April 21, 2021): e2016363118. http://dx.doi.org/10.1073/pnas.2016363118.

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The position of recombination events established along chromosomes in early prophase I and the chromosome remodeling that takes place in late prophase I are intrinsically linked steps of meiosis that need to be tightly regulated to ensure accurate chromosome segregation and haploid gamete formation. Here, we show that RAD-51 foci, which form at the sites of programmed meiotic DNA double-strand breaks (DSBs), exhibit a biased distribution toward off-centered positions along the chromosomes in wild-type Caenorhabditis elegans, and we identify two meiotic roles for chromatin-associated protein HIM-17 that ensure normal chromosome remodeling in late prophase I. During early prophase I, HIM-17 regulates the distribution of DSB-dependent RAD-51 foci and crossovers on chromosomes, which is critical for the formation of distinct chromosome subdomains (short and long arms of the bivalents) later during chromosome remodeling. During late prophase I, HIM-17 promotes the normal expression and localization of protein phosphatases GSP-1/2 to the surface of the bivalent chromosomes and may promote GSP-1 phosphorylation, thereby antagonizing Aurora B kinase AIR-2 loading on the long arms and preventing premature loss of sister chromatid cohesion. We propose that HIM-17 plays distinct roles at different stages during meiotic progression that converge to promote normal chromosome remodeling and accurate chromosome segregation.

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Xie, Haohuan, Wen Zhang, Mei Zhang, Tasneem Akhtar, Young Li, Wenyang Yi, Xiao Sun, et al. "Chromatin accessibility analysis reveals regulatory dynamics of developing human retina and hiPSC-derived retinal organoids." Science Advances 6, no. 6 (February 2020): eaay5247. http://dx.doi.org/10.1126/sciadv.aay5247.

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Retinal organoids (ROs) derived from human induced pluripotent stem cells (hiPSCs) provide potential opportunities for studying human retinal development and disorders; however, to what extent ROs recapitulate the epigenetic features of human retinal development is unknown. In this study, we systematically profiled chromatin accessibility and transcriptional dynamics over long-term human retinal and RO development. Our results showed that ROs recapitulated the human retinogenesis to a great extent, but divergent chromatin features were also discovered. We further reconstructed the transcriptional regulatory network governing human and RO retinogenesis in vivo. Notably, NFIB and THRA were identified as regulators in human retinal development. The chromatin modifications between developing human and mouse retina were also cross-analyzed. Notably, we revealed an enriched bivalent modification of H3K4me3 and H3K27me3 in human but not in murine retinogenesis, suggesting a more dedicated epigenetic regulation on human genome.

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Lim, Patrick S. L., and Eran Meshorer. "Dppa2 and Dppa4 safeguard bivalent chromatin in order to establish a pluripotent epigenome." Nature Structural & Molecular Biology 27, no. 8 (June 22, 2020): 685–86. http://dx.doi.org/10.1038/s41594-020-0453-1.

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Zhang, Zhihua, Xiaotu Ma, and Michael Q. Zhang. "Bivalent-Like Chromatin Markers Are Predictive for Transcription Start Site Distribution in Human." PLoS ONE 7, no. 6 (June 29, 2012): e38112. http://dx.doi.org/10.1371/journal.pone.0038112.

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Sachs, Michael, Courtney Onodera, Kathryn Blaschke, Kevin T. Ebata, Jun S. Song, and Miguel Ramalho-Santos. "Bivalent Chromatin Marks Developmental Regulatory Genes in the Mouse Embryonic Germline In Vivo." Cell Reports 3, no. 6 (June 2013): 1777–84. http://dx.doi.org/10.1016/j.celrep.2013.04.032.

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Myers, Christopher G., Donald E. Olins, Ada L. Olins, and Tamar Schlick. "Mesoscale Modeling of Nucleosome-Binding Antibody PL2-6: Mono- versus Bivalent Chromatin Complexes." Biophysical Journal 118, no. 9 (May 2020): 2066–76. http://dx.doi.org/10.1016/j.bpj.2019.08.019.

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Baumann, Claudia, Christopher M. Daly, Sue M. McDonnell, Maria M. Viveiros, and Rabindranath De La Fuente. "Chromatin configuration and epigenetic landscape at the sex chromosome bivalent during equine spermatogenesis." Chromosoma 120, no. 3 (January 28, 2011): 227–44. http://dx.doi.org/10.1007/s00412-010-0306-5.

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Raman, R., A. P. Singh, and I. Nanda. "DNase I nick translation in situ on meiotic chromosomes of the mouse, Mus musculus." Journal of Cell Science 90, no. 4 (August 1, 1988): 629–34. http://dx.doi.org/10.1242/jcs.90.4.629.

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DNase-I-sensitive sites have been located on the meiotic chromosomes of the mouse, Mus musculus, by the in situ DNase I nick-translation method. We find that: (1) of all the cell types studied, pachytene nuclei are the most sensitive to DNase I; (2) in diplotene the nicks occur preferentially in the vicinity of chiasmata; (3) the sex chromosomes are also sensitive to the enzyme despite their transcriptional quiescence; and (4) in the sex bivalent the nicks are primarily observed in the putative region of recombination. We conclude that, in addition to discriminating between the transcriptionally active and inactive states of chromatin, DNase I identifies recombination-specific chromatin changes in meiotic prophase.

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Marec, František, and Walther Traut. "Sex chromosome pairing and sex chromatin bodies in W–Z translocation strains of Ephestia kuehniella (Lepidoptera)." Genome 37, no. 3 (June 1, 1994): 426–35. http://dx.doi.org/10.1139/g94-060.

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Structure and pairing behavior of sex chromosomes in females of four T(W;Z) lines of the Mediterranean flour moth, Ephestia kuehniella, were investigated using light and electron microscopic techniques and compared with the wild type. In light microscopic preparations of pachytene oocytes of wild-type females, the WZ bivalent stands out by its heterochromatic W chromosome strand. In T(W;Z) females, the part of the Z chromosome that was translated onto the W chromosome was demonstrated as a distal segment of the neo-W chromosome, displaying a characteristic non-W chromosomal chromomere–interchromomere pattern. This segment is homologously paired with the corresponding part of a complete Z chromosome. In contrast with the single ball of heterochromatic W chromatin in highly polyploid somatic nuclei of wild-type females, the translocation causes the formation of deformed or fragmented W chromatin bodies, probably owing to opposing tendencies of the Z and W chromosomal parts of the neo-W. In electron microscopic preparations of microspread nuclei, sex chromosome bivalents were identified by the remnants of electron-dense heterochromatin tangles decorating the W chromosome axis, by the different lengths of the Z and W chromosome axes, and by incomplete pairing. No heterochromatin tangles were attached to the translocated segment of the Z chromosome at one end of the neo-W chromosome. Because of the homologous pairing between the translocation and the structurally normal Z chromosome, pairing affinity of sex chromosomes in T(W;Z) females is significantly improved. Specific differences observed among T(W;Z)1–4 translocations are probably due to the different lengths of the translocated segments.Key words: Mediterranean flour moth, sex chromosomes, sex chromatin, translocations, synaptonemal complexes, microspreading.

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Béguelin, Wendy, Matt Teater, Connie Corcoran, Michelle Hamline, Randy D. Gascoyne, Ross L. Levine, Omar Abdel-Wahab, et al. "A Chromatin Reader That Acts As a Key to Lock in and Coordinate Recruitment of Transcription Factors and a Novel Polycomb Complex to Bivalent Chromatin Thus Driving Formation of Germinal Centers and B-Cell Lymphomas." Blood 126, no. 23 (December 3, 2015): 434. http://dx.doi.org/10.1182/blood.v126.23.434.434.

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Abstract The EZH2 Polycomb H3K27 histone methyltransferase and the BCL6 transcriptional repressor are highly expressed in germinal center (GC) B cells and are each targeted by activating somatic mutations in DLBCL. In previous work we demonstrated that i) EZH2 is required for GC formation, ii) EZH2 Y641 somatic mutation drives GC hyperplasia and lymphomagenesis and iii) that WT and mutant EZH2 function by creating bivalent chromatin at promoters of genes that regulate cell cycle and terminal differentiation. In other work we showed that BCL6 represses gene promoters specifically by recruiting BCOR complex (a non-canonical form of PRC1 complex); and that BCL6 and EZH2 bind to many of the same promoters, although they do not physically interact. Finally we reported that the presence of both EZH2 and BCL6 was required for BCOR complex to stably associate with chromatin. This led us to hypothesize that BCL6 and EZH2 may be mutually dependent in normal and malignant B-cells. We found that conditional deletion of EZH2 from already established GC B-cells abrogates the ability of constitutive IµBCL6 expression to induce GC hyperplasia. A similar effect was observed by administering the specific EZH2 inhibitor GSK503. For the reciprocal experiments we developed two new mouse models: a conditional BCL6 knockout and a conditional EZH2Y641F knockin in the EZH2 endogenous locus. We showed that EZH2Y641F knockin mice developed GC hyperplasia, but this effect is abrogated by conditional deletion of BCL6 from established GC B cells. Given cell line data suggesting that BCOR might be important for the effect of EZH2 and BCL6 we next generated GC BCOR conditional knockout mice and observed that loss of BCOR not only disrupts GC formation but also abrogates the GC hyperplasia when crossed into the conditional EZH2Y641F knockin mice. Reversal of the EZH2Y641F knockin GC hyperplasia was also achieved by treating these mice with a novel small molecule called 1085 that potently disrupts BCL6 binding to BCOR. Notably, 1085 synergized with EZH2 inhibitors to kill DLBCL cells in vitro and eradicate DLBCL xenografts in vivo. Collectively these data show that EZH2, BCL6 and BCOR are mutually dependent both in the context of the normal GC reaction as well as in the setting of lymphoma precursor lesions driven by constitutive BCL6 expression or mutant EZH2. We next wished to determine the basic mechanism that explains the functional connection between EZH2 and BCL6-BCOR. Using ChIP-seq in primary human GC B cells we showed that there is significant overlap between BCL6-BCOR complex binding with EZH2 and bivalent chromatin. Using ChIP-re-ChIP we found that EZH2, BCOR and BCL6 are all localized to the same chromatin at bivalent gene promoters. Previously we showed that EZH2 mediated H3K27me3 is required for BCOR recruitment. However it was not clear why or how H3K27me3 is important for this effect. We postulated that a histone reader protein might bind to BCOR and recruit it to H3K27me3 marked chromatin. We therefore performed tandem affinity purification of BCOR followed by mass spectrometry to identify putative partner proteins and identified the chromodomain containing protein CBX8 as a novel BCOR partner. Notably CBX8 is the only H3K27 chromodomain protein that is upregulated in GC B cells. We confirmed endogenous BCOR-CBX8 interaction in human DLBCL cells. We showed that CBX8 is recruited to bivalent chromatin in an H3K27me3 dependent manner, and CBX8 depletion results in loss of BCOR complex assemble. Most strikingly, CBX8 knockdown was a phenocopy of EZH2 shRNA or EZH2 inhibitor. CBX8 loss resulted in derepression of EZH2 targets, and phenocopied the effect of EZH2 shRNA or inhibitors (proliferation arrest followed by plasma cell differentiation and then apoptosis). Therefore, CBX8 is shown for the first time to recruit non-canonical PRC1 and to explain how EZH2 cooperates with BCL6 to repress transcription and mediate the GC and DLBCL phenotype. PRC2 functions in a mutually interdependent manner with BCL6 to jointly enable stable association of non-canonical PRC1 complex with bivalent chromatin. In summary, our data establish a paradigm whereby EZH2 functions in a coordinate manner with transcription factors to transiently suppress genes in a cell context-specific manner relevant to its function in normal immunity as well as DLBCL. Our results also provide a rational basis for clinical translation of combined EZH2 and BCL6 inhibitors. Disclosures Levine: Foundation Medicine: Consultancy; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees.

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Mayor, Regina, Mar Muñoz, Marcel W. Coolen, Joaquin Custodio, Manel Esteller, Susan J. Clark, and Miguel A. Peinado. "Dynamics of bivalent chromatin domains upon drug induced reactivation and resilencing in cancer cells." Epigenetics 6, no. 9 (September 2011): 1138–48. http://dx.doi.org/10.4161/epi.6.9.16066.

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Matsumura, Yoshihiro, Ryo Nakaki, Takeshi Inagaki, Ayano Yoshida, Yuka Kano, Hiroshi Kimura, Toshiya Tanaka, et al. "H3K4/H3K9me3 Bivalent Chromatin Domains Targeted by Lineage-Specific DNA Methylation Pauses Adipocyte Differentiation." Molecular Cell 60, no. 4 (November 2015): 584–96. http://dx.doi.org/10.1016/j.molcel.2015.10.025.

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Trowbridge, Jennifer J., Amit U. Sinha, Scott A. Armstrong, and Stuart H. Orkin. "Haploinsufficiency of Dnmt1 Impairs Leukemia Stem Cell Function Through Derepression of Bivalent Chromatin Domains,." Blood 118, no. 21 (November 18, 2011): 3459. http://dx.doi.org/10.1182/blood.v118.21.3459.3459.

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Abstract Abstract 3459 Leukemia stem cells (LSCs) are an attractive target in treatment of many types of blood cancers. There remains an incomplete understanding of the epigenetic mechanisms driving LSC formation and maintenance, and how this compares to the epigenetic regulation of normal hematopoietic stem cells (HSCs). One of the major epigenetic modifications, DNA methylation, is catalyzed by the DNA methyltransferase enzymes Dnmt1, Dnmt3a and Dnmt3b. We observed decreased expression of Dnmt3a and Dnmt3b in LSCs isolated from a model of MLL-AF9-induced acute myeloid leukemia (AML) compared to normal HSCs. In contrast, expression of Dnmt1 was maintained in LSCs compared to HSCs, suggesting that Dnmt1 may have a critical function in the formation and maintenance of LSCs. Supporting this hypothesis, we found that conditional knockout of Dnmt1 fully ablates the development of AML. Furthermore, haploinsufficiency of Dnmt1 (Dnmt1fl/+ Mx-Cre) was sufficient to delay progression of leukemogenesis and impair LSC self-renewal. Strikingly, haploinsufficiency of Dnmt1 did not functionally alter normal hematopoiesis or HSCs, suggesting an enhanced dependence of LSCs on DNA methylation. Mechanistically, we observed that haploinsufficiency of Dnmt1 in LSCs resulted in derepression of genes that had been silenced by MLL-AF9-mediated transformation and marked by bivalent H3K27me3/H3K4me3 chromatin domains. These results suggest that the formation and maintenance of LSCs depends not only upon activation of a leukemogenic program, but also upon silencing of a specific gene signature that is active in HSCs through crosstalk between two epigenetic mechanisms, polycomb-mediated repression and DNA methylation-mediated repression. This silenced gene signature includes known and candidate tumor suppressor genes as well as genes involved in lineage restriction. These studies present evidence that distinct epigenetic regulatory mechanisms are dominant in LSCs compared to HSCs and provide novel gene candidates for targeted reactivation in AML therapy. Disclosures: Armstrong: Epizyme: Consultancy.

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Hall, Amelia Weber, Anna M. Battenhouse, Haridha Shivram, Adam R. Morris, Matthew C. Cowperthwaite, Max Shpak, and Vishwanath R. Iyer. "Bivalent Chromatin Domains in Glioblastoma Reveal a Subtype-Specific Signature of Glioma Stem Cells." Cancer Research 78, no. 10 (March 16, 2018): 2463–74. http://dx.doi.org/10.1158/0008-5472.can-17-1724.

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Maupetit-Méhouas, Stéphanie, Bertille Montibus, David Nury, Chiharu Tayama, Michel Wassef, Satya K. Kota, Anne Fogli, et al. "Imprinting control regions (ICRs) are marked by mono-allelic bivalent chromatin when transcriptionally inactive." Nucleic Acids Research 44, no. 2 (September 22, 2015): 621–35. http://dx.doi.org/10.1093/nar/gkv960.

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Trowbridge, J. J., A. U. Sinha, N. Zhu, M. Li, S. A. Armstrong, and S. H. Orkin. "Haploinsufficiency of Dnmt1 impairs leukemia stem cell function through derepression of bivalent chromatin domains." Genes & Development 26, no. 4 (February 15, 2012): 344–49. http://dx.doi.org/10.1101/gad.184341.111.

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Watson, Corey T., Giulio Disanto, Geir Kjetil Sandve, Felix Breden, Gavin Giovannoni, and Sreeram V. Ramagopalan. "Age-Associated Hyper-Methylated Regions in the Human Brain Overlap with Bivalent Chromatin Domains." PLoS ONE 7, no. 9 (September 24, 2012): e43840. http://dx.doi.org/10.1371/journal.pone.0043840.

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Journal articles on the topic 'Bivalent chromatin'

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