A bivalent chromatin structure marks key developmental genes in embryonic stem cells.

The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific modification pattern, termed "bivalent domains," consisting of large regions of H3 lysine 27 methylation harboring smaller regions of H3 lysine 4 methylation. Bivalent domains tend to coincide with TF genes expressed at low levels. We propose that bivalent domains silence developmental genes in ES cells while keeping them poised for activation. We also found striking correspondences between genome sequence and histone methylation in ES cells, which become notably weaker in differentiated cells. These results highlight the importance of DNA sequence in defining the initial epigenetic landscape and suggest a novel chromatin-based mechanism for maintaining pluripotency.

• Publication year

  2006

• Venue

  Cell

• Publication date

  2006-04-21

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/J.CELL.2006.02.041PMID 16630819
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• EPIGENETIC REGULATION OF CELLULAR MEMORY BY THE POLYCOMB AND TRITHORAX GROUP PROTEINS

  2008cited by this paper
• Mapping of genetic and epigenetic regulatory networks using microarrays.

  2005cited by this paper
• The key to development: interpreting the histone code?

  2005cited by this paper
• Niche-Independent Symmetrical Self-Renewal of a Mammalian Tissue Stem Cell

  2005influential reference
• Global and Hox-specific roles for the MLL1 methyltransferase.

  2005cited by this paper
• WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development.

  2005cited by this paper
• Mapping of genetic and epigenetic regulatory networks using microarrays

  2005cited by this paper
• Imprinted X inactivation and reprogramming in the preimplantation mouse embryo.

  2005cited by this paper
• CpG-binding Protein (CXXC Finger Protein 1) Is a Component of the Mammalian Set1 Histone H3-Lys4 Methyltransferase Complex, the Analogue of the Yeast Set1/COMPASS Complex*

  2005cited by this paper
• Core transcriptional regulatory circuitry in human embryonic stem cells.

  2005cited by this paper
• Genome sequence, comparative analysis and haplotype structure of the domestic dog

  2005influential reference
• Chd1 chromodomain links histone H3 methylation with SAGA- and SLIK-dependent acetylation

  2005cited by this paper
• A high-resolution map of active promoters in the human genome

  2005cited by this paper
• The epigenetic basis for embryonic stem cell pluripotency.

  2005cited by this paper
• Human but Not Yeast CHD1 Binds Directly and Selectively to Histone H3 Methylated at Lysine 4 via Its Tandem Chromodomains*

  2005cited by this paper
• Intergenic transcription through a polycomb group response element counteracts silencing.

  2005cited by this paper
• Genomic maps and comparative analysis of histone modifications in human and mouse.

  2005influential reference
• Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping.

  2005cited by this paper
• EZH2 and Histone 3 Trimethyl Lysine 27 Associated with Il4 and Il13 Gene Silencing in TH1 Cells*

  2005cited by this paper
• The profile of repeat‐associated histone lysine methylation states in the mouse epigenome

  2005cited by this paper
• Study of stem cell function using microarray experiments

  2005influential reference
• Disruption of LTBP-4 function reduces TGF- (cid:1) activation and enhances BMP-4 signaling in the lung

  2004cited by this paper
• Ultraconserved Elements in the Human Genome

  2004cited by this paper
• A Dynamic Switch in the Replication Timing of Key Regulator Genes in Embryonic Stem Cells upon Neural Induction

  2004cited by this paper
• Chromatin decondensation and nuclear reorganization of the HoxB locus upon induction of transcription.

  2004cited by this paper
• Disruption of LTBP-4 function reduces TGF-β activation and enhances BMP-4 signaling in the lung

  2004cited by this paper
• Gene Order and Dynamic Domains

  2004cited by this paper
• Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs.

  2004cited by this paper
• Histone variants, nucleosome assembly and epigenetic inheritance.

  2004cited by this paper
• Highly Conserved Non-Coding Sequences Are Associated with Vertebrate Development

  2004cited by this paper
• Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes

  2004influential reference
• SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex.

  2004cited by this paper
• Epigenetic regulation of mammalian genomic imprinting.

  2004cited by this paper
• Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27.

  2004cited by this paper
• Binding to Nonmethylated CpG DNA Is Essential for Target Recognition, Transactivation, and Myeloid Transformation by an MLL Oncoprotein

  2004cited by this paper
• Expression profiling and identification of novel genes involved in myogenic differentiation

  2004influential reference
• Distinct contributions of histone H3 lysine 9 and 27 methylation to locus-specific stability of polycomb complexes.

  2004cited by this paper
• Chromatin Compaction by a Polycomb Group Protein Complex

  2004cited by this paper
• Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins.

  2004cited by this paper
• Histone Code Modifications on Pluripotential Nuclei of Reprogrammed Somatic Cells

  2004cited by this paper
• Genomewide analysis of gene expression associated with Tcof1 in mouse neuroblastoma.

  2004influential reference
• Role of transposable elements in heterochromatin and epigenetic control

  2004cited by this paper
• Immunoprecipitation of native chromatin: NChIP.

  2003cited by this paper
• BMC Genomics BioMed Central Methodology article

  2003cited by this paper
• Establishment of histone h3 methylation on the inactive X chromosome requires transient recruitment of Eed-Enx1 polycomb group complexes.

  2003cited by this paper
• Scanning Human Gene Deserts for Long-Range Enhancers

  2003cited by this paper
• MLL-mediated transcriptional gene regulation investigated by gene expression profiling

  2003cited by this paper
• Methylation of histone H3 K4 mediates association of the Isw1p ATPase with chromatin.

  2003cited by this paper
• Role of Histone H3 Lysine 27 Methylation in X Inactivation

  2003cited by this paper
• Comprehensive analysis of CpG islands in human chromosomes 21 and 22

  2002cited by this paper
• Initial sequencing and comparative analysis of the mouse genome

  2002cited by this paper
• Large-Scale Transcriptional Activity in Chromosomes 21 and 22

  2002influential reference
• Short interspersed transposable elements (SINEs) are excluded from imprinted regions in the human genome

  2001cited by this paper
• Erratum: correction: Initial sequencing and analysis of the human genome

  2001cited by this paper
• Translating the Histone Code

  2001cited by this paper
• The Polycomb-Group GeneEzh2 Is Required for Early Mouse Development

  2001cited by this paper
• The Polycomb-Group Gene Ezh2 Is Required for Early Mouse Development

  2001cited by this paper
• Initial sequencing and analysis of the human genome

  2001cited by this paper
• Generation of mice from wild-type and targeted ES cells by nuclear cloning

  2000cited by this paper
• SINE Retroposons Can Be Used In Vivo as Nucleation Centers for De Novo Methylation

  2000cited by this paper
• Embryonic stem cell-derived glial precursors: a source of myelinating transplants.

  1999cited by this paper
• Binding of Trithorax and Polycomb proteins to the bithorax complex: dynamic changes during early Drosophila embryogenesis

  1998cited by this paper
• Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro.

  1996cited by this paper
• Review Stem Cells and Cancer: The Polycomb Connection

  year unknowncited by this paper

• Epigenetic and transcriptional profiling of secondary hair follicle stem cells during cashmere growth.

  2026cites this paper
• Neurogenesis and the Epigenetic Landscape: Role of Histone Modifications and Chromatin Remodeling

  2026cites this paper
• Hippocampal estrogen levels, receptor types, and epigenetics contribute to sex-specific memory vulnerabilities to concurrent acute stresses.

  2026cites this paper
• Histone H2BK120 ubiquitination modulates PRC1 activity and H2AK119ub deposition on nucleosomes

  2026cites this paper
• BRD4 represses developmental and neuronal genes through interactions with polycomb complexes

  2026cites this paper
• Cooperative and Opposing Functions of ANP32E and VPS72 Govern Gene Promoter Chromatin Status

  2026cites this paper
• ZFP161 promotes colorectal cancer progression by transcriptionally activating c-MYC.

  2026cites this paper
• Silencer-regulated circLSM14A inhibits autophagy of pulmonary artery smooth muscle cells through parental protein LSM14A.

  2026cites this paper
• Metadata assessment of non-human primate studies of AAV9 uncovers potential tissue specific variation in expression efficiency.

  2026cites this paper
• Epigenetic remodeling during early embryonic development.

  2026cites this paper
• Direct Readout of Multivalent Chromatin Reader-Nucleosome Interactions by Nucleosome Mass Spectrometry.

  2026cites this paper
• Human pluripotent stem cell models of Friedreich’s ataxia: innovations, considerations, and future perspectives

  2026cites this paper
• The Bivalent Chromatin and a Potential Silencer for Differential Expression of PRSS Genes in the Human Testis

  2026cites this paper
• Alpha-Ketoglutarate Drives an Osteogenic and Extracellular Matrix Gene Program in Periodontal Ligament Fibroblasts via Selective Reduction of H3K27me3

  2026cites this paper
• Transcriptional and epigenetic regulation of Ca2+-signaling genes in hepatitis B-derived hepatocellular carcinoma and their association with the cancer hallmarks

  2026cites this paper
• Crosstalk between EZH2 and DNA methylation mediates neuroendocrine prostate cancer lineage plasticity.

  2026cites this paper
• A Mediator-dependent hypertranscriptional program governs neural stem cell fate decisions in vivo

  2026cites this paper
• Enhancer dynamics and cellular architecture in the human spinal cord.

  2026cites this paper
• Chromatin assembly at replication forks enables differentiation of human iPSCs

  2026cites this paper
• The response to kidney injury is epigenetically regulated through the activation of bivalent genes.

  2026cites this paper
• Biochemistry and regulation of histone lysine l-lactylation

  2025cites this paper
• REST/NRSF Preserves muscle stem cell identity by repressing alternate cell fate

  2025cites this paper
• Persistent lineage plasticity driving lung cancer development and progression

  2025cites this paper
• Mechanisms and implications of epithelial cell plasticity in the bladder

  2025cites this paper
• An Epigenomic Roadmap Primes Non-Growing Oocytes for Maturation and Early Embryogenesis

  2025cites this paper
• DNA methylation at retrotransposons protects the germline by preventing NRF1-mediated activation

  2025cites this paper
• Composite transposons with bivalent histone marks function as RNA-dependent enhancers in cell fate regulation.

  2025cites this paper
• Ageing versus developmental silencing: Answers from the epigenome

  2025cites this paper
• Multicondition and multimodal temporal profile inference during mouse embryonic development

  2025cites this paper
• EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer

  2025cites this paper
• Bath: a Bayesian approach to analyze epigenetic transitions reveals a dual role of H3K27me3 in chondrogenesis

  2025cites this paper
• Transcriptional and epigenetic reprogramming, lineage plasticity and therapy resistance in prostate cancer.

  2025cites this paper
• Structure-guided design and development of cyclic peptide allosteric activators of Polycomb Repressive Complex 2

  2025cites this paper
• PRC2-mediated repression of PIF4 targets beyond the on/off switch of gene expression.

  2025cites this paper
• Age-dependent effect of environmental enrichment on the neural 3D chromatin interactome.

  2025cites this paper
• H3K4me3 binding ALFIN-LIKE proteins recruit SWR1 for gene-body deposition of H2A.Z

  2025cites this paper
• Embryonic stem cell factors DPPA2/4 facilitate a unique chromatin state in non-small cell lung cancer

  2025cites this paper
• Canonical and Variant Nucleosome Reprogramming from Sperm to Blastula.

  2025cites this paper
• The epipliancy journey: Tumor initiation at the mercy of identity crisis and epigenetic drift.

  2025cites this paper
• Stem cell culture conditions affect in vitro differentiation potential and mouse gastruloid formation

  2025cites this paper
• Chromatin and epigenetics in aging biology.

  2025cites this paper
• Identification of a chromatin regulator signature and potential candidate drugs for primary open-angle glaucoma

  2025cites this paper
• Chromatin regulation of neuronal activity-dependent gene programs in circuit formation and plasticity.

  2025cites this paper
• Histone variants: expanding the epigenetic potential of neurons one amino acid at a time.

  2025cites this paper
• PRAMEY enhances sperm-egg binding and modulates epigenetic dynamics in bovine embryogenesis

  2025cites this paper
• Fbxl10/Kdm2b is required for Kmt2b/Mll2 binding across the genome and regulates H3K4 methylation on bivalent promoters

  2025cites this paper
• Epigenetic regulation in early embryo development: from zygotic genome activation to the first lineage specification.

  2025cites this paper
• Increased matrix stiffness promotes fibrogenesis of hepatic stellate cells through AP-1-induced chromatin priming

  2025cites this paper
• BRAFV600E maintains the CpG island methylator phenotype, and DNA methylation of PRC2 targets genes in colon cancer

  2025cites this paper
• Bivalent chromatin instructs lineage specification during hematopoiesis.

  2025cites this paper
• Emerging roles of histone methylation in phytopathogenic fungi

  2025influential citation
• The role of genome-wide DNA methylation and polymorphisms in periodontitis etiology: A narrative review

  2025cites this paper
• CRISPR Screening Reveals a Novel Role for FOXH1 in Regulating Pluripotency of Porcine Embryonic Stem Cells

  2025cites this paper
• Convergent DNA Methylation Abnormalities at Bivalent Chromatin in Human Growth Disorders

  2025cites this paper
• Beyond Antagonism: IL-4 Exploits TNF signaling to Shape Its Gene Expression Signature in Monocytes and Macrophages

  2025cites this paper
• NanoTag is an improved method to map interactions between DNA and proteins not requiring IgG

  2025cites this paper
• Targets and mechanisms of epigenetic regulation in the temperate cereal vernalisation process

  2025cites this paper
• WDR-5 exhibits H3K4 methylation-independent activity during embryonic development in C. elegans

  2025cites this paper
• Complete sequencing of ape genomes

  2025cites this paper
• Safety and Efficacy of Givinostat for Patients with Muscular Dystrophy: A Systematic Review

  2025cites this paper
• Microrchidia ATPases and DNA 6mA demethylase ALKBH1 act antagonistically on PRC2 to control chromatin structure and stress tolerance

  2025cites this paper
• Validation of human sensory neurons derived from inducible pluripotent stem cells as a model for latent infection and reactivation by herpes simplex virus 1

  2025cites this paper
• Polycomb repressive complex 2 (PRC2) pathway’s role in cancer cell plasticity and drug resistance

  2025cites this paper
• Epigenetic Regulation of CD8+ Effector T Cell Differentiation by PDCD5

  2025cites this paper
• Ocelli: an open-source tool for the analysis and visualization of developmental multimodal single-cell data

  2025cites this paper
• The Multifaceted Roles of Zinc Finger Proteins in Pluripotency and Reprogramming

  2025cites this paper
• Priming enhances tolerance of Fusarium graminearum to triazole.

  2025cites this paper
• Systematic identification of regions where DNA methylation is correlated with transcription refines regulatory logic in normal and tumour tissues

  2025cites this paper
• Epigenetic control of cell identities from epiblast to gastrulation

  2025cites this paper
• Histone bivalency in CNS development

  2025influential citation
• Revisiting epigenetic regulation in cancer: Evolving trends and translational implications.

  2025cites this paper
• Heterochromatin fidelity is a therapeutic vulnerability in lymphoma and other human cancers

  2025cites this paper
• Comprehensive analysis of H3K27me3 LOCKs under different DNA methylation contexts reveal epigenetic redistribution in tumorigenesis

  2025cites this paper
• Histone Methyltransferase G9a in Primary Sensory Neurons Promotes Inflammatory Pain and Transcription of Trpa1 and Trpv1 via Bivalent Histone Modifications

  2025cites this paper
• Modelling transcription with explainable AI uncovers context-specific epigenetic gene regulation at promoters and gene bodies

  2025cites this paper
• The phenylalanine-and-glycine repeats of NUP98 oncofusions form condensates that selectively partition transcriptional coactivators.

  2025cites this paper
• Canonical and non-canonical PRC1 differentially contribute to regulation of neural stem cell fate

  2025cites this paper
• Setd2 overexpression rescues bivalent gene expression during SCNT-mediated ZGA

  2025cites this paper
• SETD1B-mediated broad H3K4me3 controls proper temporal patterns of gene expression critical for spermatid development

  2025cites this paper
• Epigenetic regulation of reprogramming and pluripotency: insights from histone modifications and their implications for cancer stem cell therapies

  2025cites this paper
• Enhanced mitochondrial function and delivery from adipose-derived stem cell spheres via the EZH2-H3K27me3-PPARγ pathway for advanced therapy

  2025cites this paper
• The Epigenetic Landscape: From Molecular Mechanisms to Biological Aging

  2025cites this paper
• The epigenetic landscape of fate decisions in T cells

  2025cites this paper
• DNMT1 inhibition reprograms T cells to NK-like cells with potent antitumor activity.

  2025cites this paper
• A combination of transcriptomics and epigenomics identifies genes and regulatory elements involved in embryonic tail development in the mouse

  2025cites this paper
• Unexpected mechanisms of sex-specific memory vulnerabilities to acute traumatic stress

  2025cites this paper
• Prevention of Transgene Silencing During Human Pluripotent Stem Cell Differentiation

  2025cites this paper
• Tumors and their microenvironments: Learning from pediatric brain pathologies

  2025cites this paper
• Kidney development at a glance: metabolic regulation of renal progenitor cells.

  2025cites this paper
• Deciphering the role of histone modifications in memory and exhausted CD8 T cells

  2025cites this paper
• Direct Readout of Multivalent Chromatin Reader-Nucleosome Interactions by Nucleosome Mass Spectrometry

  2025cites this paper
• White Adipocyte Stem Cell Expansion Through Infant Formula Feeding: New Insights into Epigenetic Programming Explaining the Early Protein Hypothesis of Obesity

  2025cites this paper
• Methyl-CpG-binding protein 2 reads histone methylation via an aromatic cage to regulate gene expression and chromatin association

  2025cites this paper
• The comprehensive transcriptomic atlas of porcine immune tissues and the peripheral blood mononuclear cell (PBMC) immune dynamics reveal core immune genes

  2025cites this paper
• Detection of histone modifications and full-length transcriptome in single cells identifies sequential epigenetic perceptiveness to lineage commitment

  2025cites this paper
• RNA m6A dynamics promote transcription and RNA stability of bivalent genes during iPSC-induced generation of human lung progenitors.

  2025cites this paper
• A dynamic histone-based chromatin regulatory toolkit underpins genome and developmental evolution in an invertebrate clade

  2025cites this paper
• In vivo transition in chromatin accessibility during differentiation of deep-layer excitatory neurons in the neocortex

  2025cites this paper
• Epigenetic Preparation of Future Gene Induction Kinetics.

  2025cites this paper
• Decoding the epigenetic and transcriptional basis of direct cardiac reprogramming

  2025cites this paper