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Results for “histone modification”

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At least 127 records · Page 7Linked to original sources
PubMed2005

Novel relationships among DNA methylation, histone modifications and gene expression in Ascobolus.

By studying Ascobolus strains methylated in various portions of the native met2 gene or of the hph transgene, we generalized our previous observation that methylation of the downstream portion of a gene promotes its stable silencing and triggers the production of truncated transcripts which rarely extend through the methylated region. In contrast, methylation of the promoter region does not promote efficient gene silencing. The chromatin state of met2 methylated strains was investigated after partial micrococcal nuclease (MNase) digestion. We show that MNase sensitive sites present along the unmethylated regions are no longer observed along the methylated ones. These chromatin changes are not resulting from the absence of transcription. They are associated, in both met2 and hph, with modifications of core histones corresponding, on the N terminus of histone H3, to an increase of dimethylation of lysine 9 and a decrease of dimethylation of lysine 4. Contrary to other organisms, these changes are independent of the transcriptional state of the genes, and furthermore, no decrease in acetylation of histone H4 is observed in silenced genes.

Acetylation↗
PubMed2025

Altered histone modifications in Aedes aegypti following Rift Valley fever virus exposure.

When arthropod-borne viruses (arboviruses) are delivered to vector mosquitoes in an infectious bloodmeal, viral components interact with host proteins to hijack cells and initiate replication. The extent to which arbovirus infection alters mosquito host transcriptional and genomic regulatory processes is currently unknown. We hypothesized that histone modifications would be altered in mosquitoes exposed to Rift Valley fever virus (RVFV MP12, Phlebovirus riftense, family Phleboviridae). We interrogated transcriptome and chromatin landscapes in Aedes aegypti midguts by performing Cleavage Under Targets and Release Using Nuclease (CUT&RUN), using H3K27ac and H3K9me3 marks. Altered H3K27ac marks were identified following RVFV MP12 exposure, as well as upon bloodfeeding alone. It took several days for differential H3K27ac marks to be associated with differentially expressed genes (DEGs) in RVFV-exposed midguts. H3K27ac peaks showed progressive depletion as infection progressed. Gene set enrichment analysis revealed that immune response transcripts were enriched at 1 and 3 dpf (days post-feeding) but depleted by 7 dpf. Hedgehog/Gli (glioma-associated oncogene homolog) signaling pathway transcripts were depleted, indicating possible viral manipulation of cellular polarization. Moreover, at 7 dpf, 7 of 102 DEGs were proximal to differentially acetylated sites in a pattern expected to favor viral propagation. However, one transcript coding for an antiviral effector (LysM-TLDc domain protein) showed significant depletion of both H3K9me3 and H3K27ac marks. Analysis of midguts after a non-infectious bloodmeal versus sugar-fed controls revealed global changes to H3K27ac and H3K9me3 marks during and following the period of bloodmeal digestion. Differential H3K27ac marks were proximal to one quarter of all DEGs at 1 dpf, consistent with an important role of H3K27ac in bloodmeal digestion. These results demonstrate that H3K27ac and H3K9me3 patterns are altered upon virus exposure in a complex interplay that favors viral replication but is also countered by host responses to limit replication.

ChIP-Seq↗
PubMed2006

Epigenetic histone modifications do not control Igkappa locus contraction and intranuclear localization in cells with dual B cell-macrophage potential.

Somatic rearrangement of the Ig genes during B cell development is believed to be controlled, at least in part, by accessibility of the loci to the recombinational machinery. Accessibility is poorly understood, but appears to be controlled by a combination of histone posttranslational modifications, large scale Ig locus contractions, and changes in intranuclear localization of the loci. These changes are regulated by developmental stage-specific as well as tissue-specific mechanisms. We previously isolated a murine B cell lymphoma line, Myc5, that can oscillate between the B cell and macrophage lineages depending upon growth conditions. This line provides an opportunity to study tissue-specific regulation of epigenetic mechanisms operating on the Ig loci. We found that when Myc5 cells are induced to differentiate from B cells into macrophages, expression of macrophage-specific transcripts was induced (M-CSFR, F4/80, and CD14), whereas B cell-specific transcripts decreased dramatically (mb-1, E47, IRF4, Pax5, and Igkappa). Loss of Igkappa transcription was associated with reduced Igkappa locus contraction, as well as increased association with heterochromatin protein-1 and association of the Igkappa locus with the nuclear periphery. Surprisingly, however, we found that histone modifications at the Igkappa locus remained largely unchanged whether the cells were grown in vivo as B cells, or in vitro as macrophages. These results mechanistically uncouple histone modifications at the Igkappa locus from changes in locus contraction and intranuclear localization.

Alleles↗
PubMed2005

Complicated tails: histone modifications and the DNA damage response.

In recent years, several ATP-dependent chromatin-remodeling complexes and covalent histone modifications have been implicated in the response to double-stranded DNA breaks (DSBs). When a DSB occurs, cells must identify the DSB, activate the DNA damage checkpoint, and repair the break. Chromatin modification appears to be important but not essential for each of these processes, yet its precise mechanistic roles are only beginning to come into focus. Here, we discuss the role of chromatin in signaling by the DNA damage checkpoint pathway.

Animals↗
PubMed2003

The NuRD complex: linking histone modification to nucleosome remodeling.

ATP-dependent nucleosome remodeling and core histone tail modifications play important roles in chromatin function. Purification and characterization of the NuRD/Mi-2 complex, which possesses both nucleosome remodeling and histone deacetylase activities, suggests that ATP-dependent nucleosome remodeling and histone tail modification can be coupled. Recent studies indicate that NuRD is an integral part of the MeCP1 complex, suggesting that nucleosome remodeling and histone deacetylation play important roles in methylated DNA silencing. Studies in Caenorhabditis elegans have revealed important functions of the NuRD complex in embryonic patterning and Ras signaling. Accumulating evidence indicates that NuRD may regulate transcription of specific genes by interacting with specific transcriptional factors. In addition, it may also participate in genome-wide transcriptional regulation through an association with histone tails.

Animals↗
PubMed2004

Structures of protein domains that create or recognize histone modifications.

DNA is packed together with histone proteins in cell nuclei to form a compact structure called chromatin. Chromatin represents a scaffold for many genetic events and shows varying degrees of condensation, including a relatively open form (euchromatin) and a highly condensed form (heterochromatin). Enzymes such as histone acetyltransferases (HATs) and methylases covalently label the amino-termini of histones, thereby creating a 'histone code' of modifications that is interpreted by the recruitment of other proteins through recognition domains. Ultimately, this network of interacting proteins is thought to control the degree of chromatin condensation so that DNA is available when it is required for genomic processes. Reviewed here are the structures of HAT and SET domains, which mediate the acetylation and methylation of histones, respectively, and bromodomains and chromodomains, which recognize the modified histones. How these structures have increased our understanding of DNA regulation is also discussed.

Acetylation↗
PubMed2002

Chromatin remodeling, histone modifications, and DNA methylation-how does it all fit together?

DNA methylation is important in the control of gene transcription and chromatin structure. The complexities of this process are just beginning to be elucidated in relationship to other epigenetic mechanisms. Exciting new research in the areas of histone methylation and chromatin remodeling make it clear just how important the connections between these various mechanisms and DNA methylation are for the control of chromosome structure and gene expression. Emerging evidence suggests that chromatin remodeling enzymes and histone methylation are essential for proper DNA methylation patterns. Other histone modifications, such as acetylation and phosphorylation, in turn, affect histone methylation and histone methylation also appears to be highly reliant on chromatin remodeling enzymes. This review will summarize what is likely only the beginning of a flood of new information that will ultimately link all epigenetic modifications of the mammalian genome. A model will also be put forth to account for how chromatin modifications lead to genomic DNA methylation patterns.

Acetylation↗
PubMed2004

The roles of histone modifications and small RNA in centromere function.

Here, epigenetic regulation of centromeric chromatin in fission yeast (Schizosaccharomyces pombe) is reviewed, focussing on the role of histone modifications and the link to RNA interference (RNAi). Fission yeast centromeres are organized into two structurally and functionally distinct domains, both of which are required for centromere function. The central core domain anchors the kinetochore structure while the flanking heterochromatin domain is important for sister centromere cohesion. The chromatin structure of both domains is regulated epigenetically. In the central core domain, the histone H3 variant Cnp1(CENP-A) plays a key role. In the flanking heterochromatin domain, histones are kept underacetylated by the histone deacetylases (HDACs) Clr3, Clr6 and Sir2, and methylated by Clr4 methyltransferase (HMTase) to create a specific binding site for the Swi6 protein. Swi6 then directly mediates cohesin binding to the centromeric heterochromatin. Recently, a surprising link was made between heterochromatin formation and RNAi.

Centromere↗
PubMed2005

Coordinated changes in DNA methylation and histone modifications regulate silencing/derepression of luteinizing hormone receptor gene transcription.

We have previously demonstrated that transcription of the luteinizing hormone receptor (LHR) gene is subject to repression by histone deacetylation at its promoter region, where a histone deacetylase (HDAC)/mSin3A complex is anchored at a proximal Sp1 site. The present studies have shown that epigenetic silencing and activation of the LHR gene is achieved through coordinated regulation at both the histone and DNA levels. The HDAC inhibitor trichostatin A (TSA) evoked robust but significantly lower activation of the LHR gene in JAR than in MCF-7 cells. This effect was localized to the 176-bp promoter region, which is highly methylated in JAR and lightly methylated in MCF-7 cells. Consequently, TSA and the DNA demethylating reagent 5-azacytidine (5-AzaC) caused marked synergistic activation of the LHR gene in JAR but not in MCF-7 cells. Multiple site-specific lysine acetylation of H3/H4 is associated with such LHR gene activation. Methylation or acetylation of H3 at K9 is present at the silenced and derepressed LHR promoter, respectively. While DNA methylation levels did not affect the histone code of the LHR gene promoter, demethylation of the promoter CpG sites was necessary for maximal stimulation of this gene. Mechanistically, the combined actions of TSA and 5-AzaC, but not either 5-AzaC or TSA alone, resulted in complete demethylation of the LHR gene promoter in JAR cells. Release of the repressive HDAC/mSin3A complex from the LHR gene promoter in both cell types required both TSA-induced changes of histone modifications and, concurrently, a demethylated promoter. Also, Dnmt1 was largely dissociated from the LHR gene promoter in the presence of TSA or TSA plus 5-AzaC, and binding of MBD2 in JAR cells was diminished upon conversion of the promoter to a demethylated state. Such changes induced a more permissive chromatin where recruitment of polymerase II and TFIIB to the promoter was significantly increased. The activated state of the LHR gene induced by TSA and 5-AzaC in JAR and MCF-7 cells was observed basally in LHR-expressing PLC cells, in which the promoter is unmethylated and associated with hyperacetylated histones. Consequently, PLC cells are unresponsive to drug treatment. These findings have elucidated a regulatory mechanism whereby concurrent dissociation of repressors and association of activators and basal transcriptional components, resulting from coordinated histone hyperacetylation and DNA demethylation, lead to derepression of the LHR gene expression.

Acetylation↗
PubMed2004

High-resolution genome-wide mapping of histone modifications.

The expression patterns of eukaryotic genomes are controlled by their chromatin structure, consisting of nucleosome subunits in which DNA of approximately 146 bp is wrapped around a core of 8 histone molecules. Post-translational histone modifications play an essential role in modifying chromatin structure. Here we apply a combination of SAGE and chromatin immunoprecipitation (ChIP) protocols to determine the distribution of hyperacetylated histones H3 and H4 in the Saccharomyces cerevisiae genome. We call this approach genome-wide mapping technique (GMAT). Using GMAT, we find that the highest acetylation levels are detected in the 5' end of a gene's coding region, but not in the promoter. Furthermore, we show that the histone acetyltransferase, GCN5p, regulates H3 acetylation in the promoter and 5' end of the coding regions. These findings indicate that GMAT should find valuable applications in mapping target sites of chromatin-modifying enzymes.

Chromatin↗
PubMed2001

A tale of histone modifications.

The modification of chromatin structure is important for a number of nuclear functions, exemplified by the regulation of transcription. This review discusses recent studies of covalent histone modifications and the enzymatic machines that generate them.

Acetylation↗
PubMed2004

Histone modification activities of JDP2 associated with retinoic acid-induced differentiation of F9 cells.

Transcription factor JDP2 served as a repressor of AP-1 and inhibited the transactivation of the c-jun gene by p300/ATF-2, by recruitment of histone deacetylase complex (HDAC3), thereby repressing the RA-induced transcription of the c-jun gene and then inhibiting the RA-mediated differentiation of F9 cells. These results suggest that HDAC3/JDP2 and p300/ATF-2 complex play a critical role in controlling the differentiation of F9 cells, in response to RA. We also found that JDP2 has the activities associated with histone binding and inhibition of histone acetyltransferase (INHAT) as well as regulation of chromatin assembly. The region that includes that includes the amino-terminal 35 amino acids adjacent to the basic region are required for histone-binding activity and the region that includes both histone-binding domain and basic region is essential for the inhibition of INHAT. Moreover, assays of nucleosome assembly in vitro demonstrated that JDP2 also has histone chaperone activity. These results revealed that JDP2 is not only a sequence specific DNA-binding protein and but also controls the transcription of AP-1 response genes by direct regulation of histone modification.

Cell Differentiation↗
PubMed2005

Epigenetic mechanism of rRNA gene silencing: temporal order of NoRC-mediated histone modification, chromatin remodeling, and DNA methylation.

Epigenetic control mechanisms silence about half of the rRNA genes in eukaryotes. Previous studies have demonstrated that recruitment of NoRC, a SNF2h-containing remodeling complex, silences rRNA gene transcription. NoRC mediates histone H4 deacetylation, histone H3-Lys9 dimethylation, and de novo DNA methylation, thus establishing heterochromatic features at the rRNA gene promoter. Here we show that inhibition of any of these activities alleviates NoRC-dependent silencing, indicating that these processes are intimately linked. We have studied the temporal order of epigenetic events at the rRNA gene promoter during gene silencing and demonstrate that recruitment of NoRC by TTF-I is a prerequisite for the deacetylation of histone H4 and the dimethylation of histone H3-Lys9. Inhibition of histone deacetylation prevents DNA methylation, while inhibition of DNA methylation does not affect histone modification. Importantly, ATP-dependent chromatin remodeling is required for methylation of a specific CpG dinucleotide within the upstream control element of the rRNA gene promoter, and this modification impairs preinitiation complex formation. The results of this study reveal a clear hierarchy of epigenetic events that control de novo DNA methylation and lead to silencing of RNA genes.

Acetylation↗
PubMed2006

Histone modification patterns associated with the human X chromosome.

X inactivation is associated with chromosome-wide establishment of inactive chromatin. Although this is classically regarded as facultative heterochromatin that is uniform in nature, the exact distribution of associated epigenetic marks is not well defined. Here we have analysed histone modifications in human somatic cells within two selected regions of the X chromosome. Intergenic, coding and promoter regions are segregated into differentially marked chromatin. H3K27me3 is most prominent in intergenic and silenced coding regions, but is associated with some active coding regions as well. Histone H3/H4 acetylation and H3K4me3 are locally enriched at promoter regions but do not necessarily mark continuing transcription. Remarkably, H3K9me3 is predominant in coding regions of active genes, a phenomenon that is not restricted to the X chromosome. These results argue against the exclusiveness of individual marks to heterochromatin or euchromatin, but rather suggest that composite patterns of interdependent or mutually exclusive modifications together signal the gene expression status.

Acetylation↗
PubMed2006

Coordinated changes of histone modifications and HDAC mobilization regulate the induction of MHC class II genes by Trichostatin A.

The deacetylase inhibitor Trichostatin A (TSA) induces the transcription of the Major Histocompatibility Class II (MHC II) DRA gene in a way independent of the master coactivator CIITA. To analyze the molecular mechanisms by which this epigenetic regulator stimulates MHC II expression, we used chromatin immunoprecipitation (ChIP) assays to monitor the alterations in histone modifications that correlate with DRA transcription after TSA treatment. We found that a dramatic increase in promoter linked histone acetylation is followed by an increase in Histone H3 lysine 4 methylation and a decrease of lysine 9 methylation. Fluorescence recovery after photobleaching (FRAP) experiments showed that TSA increases the mobility of HDAC while decreasing the mobility of the class II enhanceosome factor RFX5. These data, in combination with ChIP experiments, indicate that the TSA-mediated induction of DRA transcription involves HDAC relocation and enhanceosome stabilization. In order to gain a genome-wide view of the genes responding to inhibition of deacetylases, we compared the transcriptome of B cells before and after TSA treatment using Affymetrix microarrays. This analysis showed that in addition to the DRA gene, the entire MHC II family and the adjacent histone cluster that are located in chromosome 6p21-22 locus are strongly induced by TSA. A complex pattern of gene reprogramming by TSA involves immune recognition, antiviral, apoptotic and inflammatory pathways and extends the rationale for using Histone Deacetylase Inhibitors (HDACi) to modulate the immune response.

Acetylation↗
PubMed2005

Heterochromatin formation involves changes in histone modifications over multiple cell generations.

Stable, epigenetic inactivation of gene expression by silencing complexes involves a specialized heterochromatin structure, but the kinetics and pathway by which euchromatin is converted to the stable heterochromatin state are poorly understood. Induction of heterochromatin in Saccharomyces cerevisiae by expression of the silencing protein Sir3 results in rapid loss of histone acetylation, whereas removal of euchromatic histone methylation occurs gradually through several cell generations. Unexpectedly, Sir3 binding and the degree of transcriptional repression gradually increase for 3-5 cell generations, even though the intracellular level of Sir3 remains constant. Strains lacking Sas2 histone acetylase or the histone methylases that modify lysines 4 (Set1) or 79 (Dot1) of H3 display accelerated Sir3 accumulation at HMR or its spreading away from the telomere, suggesting that these histone modifications exert distinct inhibitory effects on heterochromatin formation. These findings suggest an ordered pathway of heterochromatin assembly, consisting of an early phase, driven by active enzymatic removal of histone acetylation and resulting in incomplete transcriptional silencing, followed by a slower maturation phase, in which gradual loss of histone methylation enhances Sir association and silencing. Thus, the transition between euchromatin and heterochromatin is gradual and requires multiple cell division cycles.

Chromatin Assembly and Disassembly↗
PubMed2006

Epigenetic regulation of tumor endothelial cell anergy: silencing of intercellular adhesion molecule-1 by histone modifications.

Tumors can escape from immunity by repressing leukocyte adhesion molecule expression on tumor endothelial cells and by rendering endothelial cells unresponsive to inflammatory activation. This endothelial cell anergy is induced by angiogenic growth factors and results in reduced leukocyte-vessel wall interactions, thereby attenuating infiltration of leukocytes into the tumor. This report describes a novel mechanism of endothelial cell anergy regulation. We recently reported that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors have angiostatic activity. Here, we studied whether epigenetic mechanisms regulate this angiogenesis-mediated escape from immunity. We found that DNMT inhibitors 5-aza-2'-deoxycytidine and zebularine, as well as HDAC inhibitor trichostatin A, reexpressed intercellular adhesion molecule-1 (ICAM-1) on tumor-conditioned endothelial cells in vitro, resulting in restored leukocyte-endothelial cell adhesion. In addition, treatment with DNMT or HDAC inhibitors in vivo also restored ICAM-1 expression on tumor endothelial cells from two different mouse tumor models. Furthermore, leukocyte-vessel wall interactions in mouse tumors were increased by these compounds, as measured by intravital microscopy, resulting in enhanced leukocyte infiltration. We show that ICAM-1 down-regulation in tumor endothelial cells is associated with ICAM-1 promoter histone H3 deacetylation and loss of histone H3 Lys(4) methylation but not with DNA hypermethylation. In conclusion, our data show that ICAM-1 is epigenetically silenced in tumor endothelial cells by promoter histone modifications, which can be overcome by DNMT and HDAC inhibitors, suggesting a new molecular mechanism based on which novel therapeutic approaches for cancer can be pursued.

Acetylation↗
PubMed2005

Histone modifications as a platform for cancer therapy.

Tumorigenesis and metastasis are a progression of events resulting from alterations in the processing of the genetic information. These alterations result from stable genetic changes (mutations) involving tumor suppressor genes and oncogenes (e.g., ras, BRAF) and potentially reversible epigenetic changes, which are modifications in gene function without a change in the DNA sequence. Mutations of genes coding for proteins that directly or indirectly influence epigenetic processes will alter the cell's gene expression program. Epigenetic mechanisms often altered in cancer cells are DNA methylation and histone modifications (acetylation, methylation, phosphorylation). This article will review the potential of these reversible epigenetic processes as targets for cancer therapies.

Chromatin↗