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Results for “repressive histone mark”

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PubMed2005

Epigenome programming by Polycomb and Trithorax proteins.

Polycomb group (PcG) and Trithorax group (TrxG) proteins work, respectively, to maintain repressed or active transcription states of developmentally regulated genes through cell division. Data accumulated in the recent years have increased our understanding of the mechanisms by which PcG and TrxG proteins regulate gene expression. The discovery that histone methylation can serve as a specific mark for PcG and TrxG complexes has provided new insight into the mechanistic function of this cell-memory system.

Animals↗

PubMed2006

Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state.

Histone H3 lysine 9 (H3K9) and lysine 27 (H3K27) trimethylation are properties of stably silenced heterochromatin whereas H3K9 dimethylation (H3K9me2) is important for euchromatic gene repression. In colorectal cancer cells, all of these marks, as well as the key enzymes which establish them, surround the hMLH1 promoter when it is DNA hypermethylated and aberrantly silenced, but are absent when the gene is unmethylated and fully expressed in a euchromatic state. When the aberrantly silenced gene is DNA demethylated and reexpressed following 5-aza-2'-deoxycytidine treatment, H3K9me1 and H3K9me2 are the only silencing marks that are lost. A series of other silenced and DNA hypermethylated gene promoters behave identically even when the genes are chronically DNA demethylated and reexpressed after genetic knockout of DNA methyltransferases. Our data indicate that when transcription of DNA hypermethylated genes is activated in cancer cells, their promoters remain in an environment with certain heterochromatic characteristics. This finding has important implications for the translational goal of reactivating aberrantly silenced cancer genes as a therapeutic maneuver.

Adaptor Proteins, Signal Transducing↗

PubMed1984

Histone-H1-dependent chromatin superstructures and the suppression of gene activity.

I have identified a chromatin particle containing DNA as large as 20-40 kb that migrates as a discrete entity on agarose gels. With increasing nuclease digestion, the particle becomes cleaved in the linker regions between nucleosomes, but remains intact, probably held together by the outer histones, H1 and H5. By hybridization analysis, inactive genes are found in these particles. Active genes (and their flanking sequences) are also found in particles containing H1 and H5, but in contrast to inactive supranucleosome particles, active polynucleosome particles are not held together after cleavage of linker DNA. This suggests that H1 cross-links adjacent nucleosomes in inactive regions and that H1 is bound differently in expressed regions. The results raise the possibility that the marked degree of suppression of repressed, tissue-specific genes may be determined, in part, by their assembly into these inactive supranucleosome structures.

Animals↗

PubMed2006

Recruitment of the SWI/SNF protein Brg1 by a multiprotein complex effects transcriptional repression in murine erythroid progenitors.

SWI/SNF complexes are involved in both activation and repression of transcription. While one of two homologous ATPases, Brg1 [Brm (Brahma)-related gene 1] or Brm, is required for their chromatin remodelling function, less is known about how these complexes are recruited to DNA. We recently established that a DNA-binding complex containing TAL1/SCL, E47, GATA-1, LMO2 and Ldb1 stimulates P4.2 (protein 4.2) transcription in erythroid progenitors via two E box-GATA elements in the gene's proximal promoter. We show here that the SWI/SNF protein Brg1 is also associated with this complex and that both the E box and GATA DNA-binding sites in these elements are required for Brg1 recruitment. Further, Brg1 occupancy of the P4.2 promoter decreased with terminal erythroid differentiation in association with increased P4.2 transcription, while enforced expression of Brg1 in murine erythroleukaemia cells reduced P4.2 gene expression. Overexpression of Brg1 was associated with increased occupancy of the P4.2 promoter by the nuclear co-repressor mSin3A and HDAC2 (histone deacetylase 2) and with reduced histone H3 and H4 acetylation. Finally, a specific HDAC inhibitor attenuated Brg1-directed repression of P4.2 promoter activity in transfected cells. These results provide insight into the mechanism by which SWI/SNF proteins are recruited to promoters and suggest that transcription of P4.2, and most likely other genes, is actively repressed until the terminal differentiation of erythroid progenitors.

Acetylation↗

PubMed2005

Histone deacetylase inhibitor Trichostatin A reduces anti-DNA autoantibody production and represses IgH gene transcription.

Systemic lupus erythematosus is characterized by the presence of autoantibodies and hypergammaglobulinemia. To investigate the role of histone deacetylases (HDACs) in the production of autoantibody and immunoglobulin, we examined the effect of Trichostatin A (TSA), a specific inhibitor of HDACs, on anti-DNA autoantibody production and IgH gene transcription. Our results showed that inhibition of HDAC activity by TSA markedly reduced anti-DNA autoantibody production by T347 cells either by inducing apoptosis or in an apoptosis-independent manner, suggesting that TSA might be useful for treating certain autoimmune diseases. Moreover, we found that TSA strongly inhibited germline and post-switch immunoglobulin transcripts in T347 cells and in primary splenic B cells of MRL-lpr mice. Reporter gene analysis demonstrated that both Emu and 3'-IgH enhancer activities were repressed significantly by TSA-mediated HDAC inhibition. Furthermore, we observed that HDAC1 was recruited to the 3'-IgH enhancer hs1,2 as determined by chromatin immunoprecipitation assays. Over-expression of HDAC1 increased the activity of IgH enhancers, especially 3'-IgH enhancers. These findings implicate HDAC in the IgH gene transcription via activation of 3'-IgH enhancers.

Animals↗

PubMed2006

Clustered DNA motifs mark X chromosomes for repression by a dosage compensation complex.

Gene expression in metazoans is regulated not only at the level of individual genes but also in a coordinated manner across large chromosomal domains (for example centromeres, telomeres and imprinted gene clusters) and along entire chromosomes (for example X-chromosome dosage compensation). The primary DNA sequence usually specifies the regulation of individual genes, but the nature of cis-acting information that controls genes over large regions has been elusive: higher-order DNA structure, specific histone modifications, subnuclear compartmentalization and primary DNA sequence are possibilities. One paradigm of chromosome-wide gene regulation is Caenorhabditis elegans dosage compensation in which a large dosage compensation complex (DCC) is targeted to both X chromosomes of hermaphrodites to repress transcript levels by half. This essential process equalizes X-linked gene expression between the sexes (XO males and XX hermaphrodites). Here we report the discovery and dissection of cis-acting sites that mark nematode X chromosomes as targets for gene repression by the DCC. These rex (recruitment element on X) sites are widely dispersed along X and reside in promoters, exons and intergenic regions. rex sites share at least two distinct motifs that act in combination to recruit the DCC. Mutating these motifs severely reduces or abolishes DCC binding in vivo, demonstrating the importance of primary DNA sequence in chromosome-wide regulation. Unexpectedly, the motifs are not enriched on X, but altering motif numbers within rex sites demonstrates that motif co-occurrence in unusually high densities is essential for optimal DCC recruitment. Thus, X-specific repression is established through sequences not specific to X. The distribution of common motifs provides the foundation for repression along an entire chromosome.

Animals↗

PubMed2006

Profile of histone lysine methylation across transcribed mammalian chromatin.

Complex patterns of histone lysine methylation encode distinct functions within chromatin. We previously reported that trimethylation of lysine 9 of histone H3 (H3K9) occurs at both silent heterochromatin and at the transcribed regions of active mammalian genes, suggesting that the extent of histone lysine methylation involved in mammalian gene activation is not completely defined. To identify additional sites of histone methylation that respond to mammalian gene activity, we describe here a comparative assessment of all six known positions of histone lysine methylation and relate them to gene transcription. Using several model loci, we observed high trimethylation of H3K4, H3K9, H3K36, and H3K79 in the transcribed region, consistent with previous findings. We identify H4K20 monomethylation, a modification previously linked with repression, as a mark of transcription elongation in mammalian cells. In contrast, H3K27 monomethylation, a modification enriched at pericentromeric heterochromatin, was observed broadly distributed throughout all euchromatic sites analyzed, with selective depletion in the vicinity of the transcription start sites at active genes. Together, these results underscore that similar to other described methyl-lysine modifications, H4K20 and H3K27 monomethylation are versatile and dynamic with respect to gene activity, suggesting the existence of novel site-specific methyltransferases and demethylases coupled to the transcription cycle.

Chromatin↗

PubMed2004

The Yaf9 component of the SWR1 and NuA4 complexes is required for proper gene expression, histone H4 acetylation, and Htz1 replacement near telomeres.

Yaf9, Taf14, and Sas5 comprise the YEATS domain family in Saccharomyces cerevisiae, which in humans includes proteins involved in acute leukemias. The YEATS domain family is essential, as a yaf9Delta taf14Delta sas5Delta triple mutant is nonviable. We verify that Yaf9 is a stable component of NuA4, an essential histone H4 acetyltransferase complex. Yaf9 is also associated with the SWR1 complex, which deposits the histone H2A variant Htz1. However, the functional contribution of Yaf9 to these complexes has not been determined. Strains lacking YAF9 are sensitive to DNA-damaging agents, cold, and caffeine, and the YEATS domain is required for full Yaf9 function. NuA4 lacking Yaf9 retains histone acetyltransferase activity in vitro, and Yaf9 does not markedly reduce bulk H4 acetylation levels, suggesting a role for Yaf9 in the targeting or regulation of NuA4. Interestingly, yaf9Delta strains display reduced transcription of genes near certain telomeres, and their repression is correlated with reduced H4 acetylation, reduced occupancy by Htz1, and increased occupancy by the silencing protein Sir3. Additionally, the spectra of phenotypes, genes, and telomeres affected in yaf9Delta and htz1Delta strains are significantly similar, further supporting a role for Yaf9 in Htz1 deposition. Taken together, these data indicate that Yaf9 may function in NuA4 and SWR1 complexes to help antagonize silencing near telomeres.

Acetylation↗

PubMed2006

Histone modification and the control of heterochromatic gene silencing in Drosophila.

Covalent modifications of histones index structurally and functionally distinct chromatin domains in eukaryotic nuclei. Drosophila with its polytene chromosomes and developed genetics allows detailed cytological as well as functional analysis of epigenetic histone modifications involved in the control of gene expression pattern during development. All H3K9 mono- and dimethylation together with all H3K27 methylation states and H4K20 trimethylation are predominant marks of pericentric heterochromatin. In euchromatin, bands and interbands are differentially indexed. H3K4 and H3K36 methylation together with H3S10 phosphorylation are predominant marks of interband regions whereas in bands different H3K27 and H4K20 methylation states are combined with acetylation of H3K9 and H3K14. Genetic dissection of heterochromatic gene silencing in position-effect variegation (PEV) by Su(var) and E(var) mutations allowed identification and functional analysis of key factors controlling the formation of heterochromatin. SU(VAR)3-9 association with heterochromatic sequences followed by H3K9 methylation initiates the establishment of repressive SU(VAR)3-9/HP1/SU(VAR)3-7 protein complexes. Differential enzymatic activities of novel point mutants demonstrate that the silencing potential of SU(VAR)3-9 is mainly determined by the kinetic properties of the HMTase reaction. In Su(var)3-9ptn a significantly enhanced enzymatic activity results in H3K9 hypermethylation, enhanced gene silencing and extensive chromatin compaction. Mutations in factors controlling active histone modification marks revealed the dynamic balance between euchromatin and heterochromatin. Further analysis and definition of Su(var) and E(var) genes in Drosophila will increase our understanding of the molecular hierarchy of processes controlling higher-order structures in chromatin.

Amino Acid Sequence↗

PubMed2026

Loss of SUMOylation drives aberrant PRC1 clustering and 3D genome rewiring independent of H3K27me3.

Polycomb repressive complex 1 (PRC1) forms nuclear condensates that organize target chromatin domains. SUMOylation modulates PRC1 clustering, but its impact on condensate properties and 3D genome architecture remains unclear. Here, we show that depletion of small ubiquitin-like modifier (SUMO) in Drosophila wing imaginal discs transforms PRC1 condensates into large structures with reduced molecular dynamics. Biophysical modeling suggests that the changes in PRC1 self-interactions are responsible for the formation of large PRC1 condensates when SUMO is depleted. Interestingly, this biophysical reorganization occurs without global loss of the H3K27me3 mark. Instead, Hi-C reveals widespread rewiring of topologically associating domain (TAD) interactions. PRC1-bound TADs lose specific long-range contacts with each other while gaining ectopic interactions with active chromatin. These topological shifts correlate with gene misregulation independently of changes in Polycomb histone modifications. Our results establish SUMOylation as a critical regulator of PRC1 condensates, demonstrating that post-translational control of biomolecular condensation modulates 3D genome architecture and transcriptional output through mechanisms separable from histone mark deposition.

Animals↗

PubMed2002

The many faces of histone lysine methylation.

Diverse post-translational modifications of histone amino termini represent an important epigenetic mechanism for the organisation of chromatin structure and the regulation of gene activity. Within the past two years, great progress has been made in understanding the functional implications of histone methylation; in particular through the characterisation of histone methyltransferases that direct the site-specific methylation of, for example, lysine 9 and lysine 4 positions in the histone H3 amino terminus. All known histone methyltransferases of this type contain the evolutionarily conserved SET domain and appear to be able to stimulate either gene repression or gene activation. Methylation of H3 Lys9 and Lys4 has been visualised in native chromatin, indicating opposite roles in structuring repressive or accessible chromatin domains. For example, at the mating-type loci in Schizosaccharomyces pombe, at pericentric heterochromatin and at the inactive X chromosome in mammals, striking differences between these distinct marks have been observed. H3 Lys9 methylation is also important to direct additional epigenetic signals such as DNA methylation--for example, in Neurospora crassa and in Arabidopsis thaliana. Together, the available data strongly establish histone lysine methylation as a central modification for the epigenetic organisation of eukaryotic genomes.

Animals↗

PubMed2004

Juvenile hormones antagonize ecdysone actions through co-repressor recruitment to EcR/USP heterodimers.

Insect development is controlled by the combined actions of ecdysteroid and juvenile hormones. Transcriptional control by ecdysteroid hormones is mediated via two nuclear receptor superfamily members, ecdysone receptor (EcR) and its heterodimeric partner, ultraspiracle (USP). Although the ecdysteroid hormone 20-hydroxyecdysone acts as an EcR ligand and activates transcription through EcR/USP heterodimers, the activity of juvenile hormones, such as Juvenile hormone III (JH III), and methoprenic acid (MA) via USP remains unclear. Here, we demonstrate that juvenile hormones act as USP ligands and exhibit suppressive effects on ecdysone-dependent EcR transactivation. JH III- and MA-bound USP markedly repressed ecdysone-dependent EcR transactivation through shifting of the USP ligand-binding domain alpha-helix 12 without affecting EcR/USP heterodimerization or DNA binding. Moreover, transcriptional repression by USP ligands was attenuated by a histone deacetylation inhibitor. Our results suggested that juvenile hormones serve as USP ligands that antagonize EcR-mediated ecdysone actions through the recruitment of histone deacetylase complexes.

Animals↗

PubMed2004

Loss of estrogen receptor signaling triggers epigenetic silencing of downstream targets in breast cancer.

Alterations in histones, chromatin-related proteins, and DNA methylation contribute to transcriptional silencing in cancer, but the sequence of these molecular events is not well understood. Here we demonstrate that on disruption of estrogen receptor (ER) alpha signaling by small interfering RNA, polycomb repressors and histone deacetylases are recruited to initiate stable repression of the progesterone receptor (PR) gene, a known ERalpha target, in breast cancer cells. The event is accompanied by acquired DNA methylation of the PR promoter, leaving a stable mark that can be inherited by cancer cell progeny. Reestablishing ERalpha signaling alone was not sufficient to reactivate the PR gene; reactivation of the PR gene also requires DNA demethylation. Methylation microarray analysis further showed that progressive DNA methylation occurs in multiple ERalpha targets in breast cancer genomes. The results imply, for the first time, the significance of epigenetic regulation on ERalpha target genes, providing new direction for research in this classical signaling pathway.

Base Sequence↗

PubMed2000

Identification of a transcriptional repressor related to the noncatalytic domain of histone deacetylases 4 and 5.

Histone deacetylases (HDACs) are involved in regulating transcription by modifying the core histones of the nucleosome. To date, six HDACs have been identified in mammalian cells: the yeast RPD3 homologs HDAC1, 2, and 3 and the yeast HDA1 homologs HDAC4, 5, and 6. HDAC4 and HDAC5 contain a noncatalytic N-terminal domain. Herein, we report the identification of a protein HDRP (HDAC-related protein) that shares 50% identity in deduced amino acid sequence to the noncatalytic N-terminal domain of HDAC4 and 5. The steady-state levels of HDRP mRNA are high in human brain, heart, and skeletal muscle and low in the several other tissues. HDRP has an apparent molecular mass of approximately 75 kDa. HDRP does not possess intrinsic HDAC activity but forms complexes with both HDAC1 and HDAC3. HDRP represses both basal and activated transcription in transient transfection assays when tethered to DNA as a Gal4-fusion protein. HDAC inhibitors do not reverse transcriptional repression mediated by Gal4-HDRP. Thus, HDRP is a transcriptional repressor and can repress transcription in the presence of HDAC inhibitors.

Amino Acid Sequence↗

PubMed2005

Functional interaction between the Drosophila knirps short range transcriptional repressor and RPD3 histone deacetylase.

Knirps and other short range transcriptional repressors play critical roles in patterning the early Drosophila embryo. These repressors are known to bind the C-terminal binding protein corepressor, but their mechanism of action is poorly understood. We purified functional recombinant Knirps protein from transgenic embryos to identify possible cofactors that contribute to the activity of this protein. The protein migrates in a complex of approximately 450 kDa and was found to copurify with the Rpd3 histone deacetylase protein during a double affinity purification procedure. Association of Rpd3 with Knirps was dependent on the presence of the C-terminal binding protein-dependent repression domain of Knirps. Previous studies of an rpd3 mutant had not shown defects in the pattern of expression of even-skipped, a target of the Knirps repressor. However, in embryos doubly heterozygous for knirps and rpd3, a marked increase in the frequency of defects in the Knirps-regulated posterior domain of even-skipped expression was found, indicating that Rpd3 contributes to Knirps repression activity in vivo. This finding implicates deacetylation in the mechanism of short range repression in Drosophila.

Animals↗

PubMed2003

Critical role of the transcriptional repressor neuron-restrictive silencer factor in the specific control of connexin36 in insulin-producing cell lines.

Connexin36 (Cx36) is specifically expressed in neurons and in pancreatic beta-cells. Cx36 functions as a critical regulator of insulin secretion and content in beta-cells. In order to identify the molecular mechanisms that control the beta-cell expression of Cx36, we initiated the characterization of the human 5' regulatory region of the CX36 gene. A 2043-bp fragment of the human CX36 promoter was identified from a human BAC library and fused to a luciferase reporter gene. This promoter region was sufficient to confer specific expression to the reporter gene in insulin-secreting cell lines. Within this 5' regulatory region, a putative neuron-restrictive silencer element conserved between rodent and human species was recognized and binds the neuron-restrictive silencing factor (NRSF/REST). This factor is not expressed in insulin-secreting cells and neurons; it functions as a potent repressor through the recruitment of histone deacetylase to the promoter of neuronal genes. The NRSF-mediated repression of Cx36 in HeLa cells was abolished by trichostatin A, confirming the functional importance of histone deacetylase activity. Ectopic expression, by viral gene transfer, of NRSF/REST in different insulin-secreting beta-cell lines induced a marked reduction in Cx36 mRNA and protein content. Moreover, mutations in the Cx36 neuron-restrictive silencer element relieved the low transcriptional activity of the human CX36 promoter observed in HeLa cells and in INS-1 cells expressing NRSF/REST. The data showed that cx36 gene expression in insulin-producing beta-cell lines is strictly controlled by the transcriptional repressor NRSF/REST indicating that Cx36 participates to the neuronal phenotype of the pancreatic beta-cells.

Adenoviridae↗

PubMed2006

Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer.

Many genes associated with CpG islands undergo de novo methylation in cancer. Studies have suggested that the pattern of this modification may be partially determined by an instructive mechanism that recognizes specifically marked regions of the genome. Using chromatin immunoprecipitation analysis, here we show that genes methylated in cancer cells are specifically packaged with nucleosomes containing histone H3 trimethylated on Lys27. This chromatin mark is established on these unmethylated CpG island genes early in development and then maintained in differentiated cell types by the presence of an EZH2-containing Polycomb complex. In cancer cells, as opposed to normal cells, the presence of this complex brings about the recruitment of DNA methyl transferases, leading to de novo methylation. These results suggest that tumor-specific targeting of de novo methylation is pre-programmed by an established epigenetic system that normally has a role in marking embryonic genes for repression.

Caco-2 Cells↗

PubMedDate not supplied

The molecular foundations of the maternal to zygotic transition in the preimplantation embryo.

The maternal to zygotic transition is the first major transition that occurs following fertilization, and entails a dramatic reprogramming of gene expression that is essential for continued development. Although the major reprogramming of gene expression occurs during the 2-cell stage, transcription is evident in the 1-cell embryo, with the male pronucleus supporting a significantly higher level of transcription than the female pronucleus. This difference is likely due to differences in chromatin structure as a consequence of the protamine-histone exchange. Although the 1-cell embryo is transcriptionally competent, transcription and translation appear uncoupled. This transcription, however, may mark promoters for efficient utilization in the 2-cell embryo. Genome activation in the 2-cell embryo is accompanied by a requirement for an enhancer for efficient transcription and the more efficient utilization of TATA-less promoters. These changes in promoter utilization could contribute substantially to the reprogramming of gene expression. Superimposed on genome activation is the development of a chromatin-mediated transcriptionally repressive state that is relieved by either inducing histone hyperacetylation or inhibiting the second round of DNA replication. Since genome activation appears to be a relatively opportunistic process, the development of the transcriptionally repressive state may be a major determinant in establishing the appropriate gene expression profile that is essential for continued development.

Animals↗