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Results for “Histone Modifications”

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PubMed2005

Repair of DNA lesions in chromosomal DNA impact of chromatin structure and Cockayne syndrome proteins.

Decondensation of chromatin is essential to facilitate access to DNA metabolizing processes such as transcription and DNA repair. Disruption of histone-DNA contacts by histone modification or by ATP dependent chromatin remodelling allows DNA-binding proteins to compete with histones for DNA. The efficiency of global genome nucleotide excision repair (GGR) that removes a variety of helix distorting DNA lesions is known to be affected by chromatin structure most notably demonstrated by the slow repair of heterochromatin. In addition, the efficiency of GGR to repair lesions in transcriptionally active genes requires functional CSA and B proteins. We found that repair of UV-photolesions in both strands of the active adenosine deaminase gene was delayed in CS cells when compared to normal human fibroblasts. We suggest that the lack of transcription recovery characteristic for CS cells exposed to DNA damaging agents, might lead to changes in the chromatin structure of active genes, causing less efficient repair of lesions in these genes when compared to normal cells.

Chromatin↗
PubMed1991

A phosphatase inhibitor enhances the DNase I sensitivity of active chromatin.

Although it is well-known that active domains of chromatin have elevated DNase I sensitivity, it can be difficult to observe preferential sensitivity in many cell types. We show that the DNase I sensitivity of active chromatin is enhanced some 10-fold by treating nuclei with the phosphatase inhibitor p-(chloromercuri)benzenesulfonic acid (CMBS) whereas DNase I sensitivity in inactive domains is only 3-fold higher. We further show that CMBS-enhanced DNase I sensitivity is associated with at least two histone modifications. First, the negatively charged CMBS molecule becomes covalently attached to the thiol groups on histone H3. Second, histone H2A phosphorylation is significantly elevated in treated nuclei. The phosphorylation data along with other results point to the possibility that H2A phosphorylation plays a role in enhancing preferential DNase I sensitivity. Whatever the mechanism, CMBS treatment of nuclei followed by DNase I digestion provides a novel and reproducible assay for probing the chromatin structure of active domains.

4-Chloromercuribenzenesulfonate↗
PubMed2005

A variable number of tandem repeats polymorphism in an E2F-1 binding element in the 5' flanking region of SMYD3 is a risk factor for human cancers.

Histone modification is a crucial step in transcriptional regulation, and deregulation of the modification process is important in human carcinogenesis. We previously reported that upregulation of SMYD3, a histone methyltransferase, promoted cell growth in human colorectal and hepatocellular carcinomas. Here we report significant associations between homozygosity with respect to an allele with three tandem repeats of a CCGCC unit in the regulatory region of SMYD3 and increased risk of colorectal cancer (P = 9.1 x 10(-6), odds ratio = 2.58), hepatocellular carcinoma (P = 2.3 x 10(-8), odds ratio = 3.50) and breast cancer (P = 7.0 x 10(-10), odds ratio = 4.48). This tandem-repeat sequence is a binding site for the transcriptional factor E2F-1. In a reporter assay, plasmids containing three repeats of the binding motif (corresponding to the high-risk allele) had higher activity than plasmids containing two repeats (the low-risk allele). These data suggest that the common variable number of tandem repeats polymorphism in SMYD3 is a susceptibility factor for some types of human cancer.

5' Flanking Region↗
PubMed2003

Xenopus transcription factor IIIA and the 5S nucleosome: development of a useful in vitro system.

5S RNA genes in Xenopus are regulated during development via a complex interplay between assembly of repressive chromatin structures and productive transcription complexes. Interestingly, 5S genes have been found to harbor powerful nucleosome positioning elements and therefore have become an important model system for reconstitution of eukaryotic genes into nucleosomes in vitro. Moreover, the structure of the primary factor initiating transcription of 5S DNA, transcription factor IIIA, has been extensively characterized. This has allowed for numerous studies of the effect of nucleosome assembly and histone modifications on the DNA binding activity of a transcription factor in vitro. For example, linker histones bind 5S nucleosomes and repress TFIIIA binding in vitro in a similar manner to that observed in vivo. In addition, TFIIIA binding to nucleosomes assembled with 5S DNA is stimulated by acetylation or removal of the core histone tail domains. Here we review the development of the Xenopus 5S in vitro system and discuss recent results highlighting new aspects of transcription factor - nucleosome interactions,

Animals↗
PubMed2006

The histone methyltransferase MLL is an upstream regulator of endothelial-cell sprout formation.

Posttranslational histone modification by acetylation or methylation regulates gene expression. Here, we investigated the role of the histone lysine methyltransferase MLL for angiogenic functions in human umbilical vein endothelial cells. Suppression of MLL expression by siRNA or incubation with the pharmacologic methyltransferase inhibitor 5'-deoxy-5'-(methylthio)adenosine significantly decreased endothelial-cell migration and capillary sprout formation, indicating that methyltransferase activity is required for proangiogenic endothelial-cell functions. Because the expression of homeodomain transcription factors (Hox) is regulated by MLL, we elucidated the role of Hox gene expression. MLL silencing was associated with reduced mRNA and protein expression of HoxA9 and HoxD3, whereas HoxB3, HoxB4, HoxB5, and HoxB9 were not altered. Overexpression of HoxA9 or HoxD3 partially compensated for impaired migration in MLL siRNA-transfected endothelial cells, suggesting that HoxA9 and HoxD3 both contribute to MLL-dependent migration. As a potential underlying mechanism, MLL siRNA down-regulated mRNA and protein levels of the HoxA9-dependent axon guidance factor EphB4. In contrast, MLL knockdown effects on capillary sprouting were not rescued by HoxA9 or HoxD3 overexpression, indicating that MLL affects additional targets required for 3-dimensional sprout formation. We conclude that MLL regulates endothelial-cell migration via HoxA9 and EphB4, whereas sprout formation requires MLL-dependent signals beyond HoxA9 and HoxD3.

Cell Movement↗
PubMed2025

Analog epigenetic memory revealed by targeted chromatin editing.

Cells store information by means of chromatin modifications that persist through cell divisions and can hold gene expression silenced over generations. However, how these modifications may maintain other gene expression states has remained unclear. This study shows that chromatin modifications can maintain a wide range of gene expression levels over time, thus uncovering analog epigenetic memory. By engineering a genomic reporter and epigenetic effectors, we tracked the gene expression dynamics following targeted perturbations to the chromatin state. We found that distinct grades of DNA methylation led to corresponding, persistent gene expression levels. Altering the DNA methylation grade, in turn, resulted in permanent loss of gene expression memory. Consistent with experiments, our chromatin modification model indicates that analog memory arises when the positive feedback between DNA methylation and repressive histone modifications is lacking. This discovery will lead to a deeper understanding of epigenetic memory and to new tools for synthetic biology.

Epigenesis, Genetic↗
PubMed1998

Hormone action and chromatin remodelling.

Current attention in transcriptional regulation is focused on the properties of coactivators and corepressors that mediate communication between sequence-specific transcription factors, the basal transcriptional machinery and the chromatin environment. Nuclear and steroid hormone receptors represent the best-understood transcription factors that utilize coactivators and corepressors. This review considers the access of these receptors to chromatin, the modifications of chromatin structure that the receptors instigate and the implications for transcriptional control. Nucleosome positioning and targeted histone modification emerge as central controlling elements for gene expression.

Chromatin↗
PubMed2004

Distribution and dynamics of chromatin modification induced by a defined DNA double-strand break.

BACKGROUND: In response to DNA double-strand breaks (DSBs), eukaryotic cells rapidly phosphorylate histone H2A isoform H2AX at a C-terminal serine (to form gamma-H2AX) and accumulate repair proteins at or near DSBs. To date, these events have been defined primarily at the resolution of light microscopes, and the relationship between gamma-H2AX formation and repair protein recruitment remains to be defined. RESULTS: We report here the first molecular-level characterization of regional chromatin changes that accompany a DSB formed by the HO endonuclease in Saccharomyces cerevisiae. Break induction provoked rapid gamma-H2AX formation and equally rapid recruitment of the Mre11 repair protein. gamma-H2AX formation was efficiently promoted by both Tel1p and Mec1p, the yeast ATM and ATR homologs; in G1-arrested cells, most gamma-H2AX formation was dependent on Tel1 and Mre11. gamma-H2AX formed in a large (ca. 50 kb) region surrounding the DSB. Remarkably, very little gamma-H2AX could be detected in chromatin within 1-2 kb of the break. In contrast, this region contains almost all the Mre11p and other repair proteins that bind as a result of the break. CONCLUSIONS: Both Mec1p and Tel1p can respond to a DSB, with distinct roles for these checkpoint kinases at different phases of the cell cycle. Part of this response involves histone phosphorylation over large chromosomal domains; however, the distinct distributions of gamma-H2AX and repair proteins near DSBs indicate that localization of repair proteins to breaks is not likely to be the main function of this histone modification.

Chromatin↗
PubMed2006

Histone mediated gene activation in Toxoplasma gondii.

DNA processes, including transcriptional activation, are largely governed by histone modifications. For most eukaryotes, chromatin-remodeling machines have been identified that move, replace, or decorate histones. Recent studies have shed some important light on similar machinery operating in apicomplexan parasites, including the opportunistic pathogen Toxoplasma gondii. Here we present a synthesis of the current knowledge of histone mediated gene expression in Toxoplasma, particularly in the context of parasite differentiation.

Animals↗
PubMed2004

The RING domain of Mdm2 mediates histone ubiquitylation and transcriptional repression.

Histone modifications play a pivotal role in regulating transcription and other chromatin-associated processes. In yeast, histone H2B monoubiquitylation affects gene silencing. However, mammalian histone ubiquitylation remains poorly understood. We report that the Mdm2 oncoprotein, a RING domain E3 ubiquitin ligase known to ubiquitylate the p53 tumor suppressor protein, can interact directly with histones and promote in vitro monoubiquitylation of histones H2A and H2B. Moreover, Mdm2 induces H2B monoubiquitylation in vivo. Endogenous Mdm2 is tethered in vivo, presumably via p53, to chromatin comprising the p53-responsive p21(waf1) promoter, and Mdm2 overexpression enhances protein ubiquitylation in the vicinity of a p53 binding site within that promoter. Moreover, when recruited to a promoter in the absence of p53, Mdm2 can repress transcription dependently on its RING domain, suggesting that its E3 activity contributes to repression. Histone ubiquitylation may thus constitute a novel mechanism of transcriptional repression by Mdm2, possibly underlying some of its oncogenic activities.

Cell Line↗
PubMed2006

Drosophila Rtf1 functions in histone methylation, gene expression, and Notch signaling.

The Rtf1 subunit of the Paf1 complex is required for proper monoubiquitination of histone H2B and methylation of histone H3 on lysines 4 (H3K4) and 79 in yeast Saccharomyces cerevisiae. Using RNAi, we examined the role of Rtf1 in histone methylation and gene expression in Drosophila melanogaster. We show that Drosophila Rtf1 (dRtf1) is required for proper gene expression and development. Furthermore, we show that RNAi-mediated reduction of dRtf1 results in a reduction in histone H3K4 trimethylation levels on bulk histones and chromosomes in vivo, indicating that the histone modification pathway via Rtf1 is conserved among yeast, Drosophila, and human. Recently, it was demonstrated that histone H3K4 methylation mediated via the E3 ligase Bre1 is critical for transcription of Notch target genes in Drosophila. Here we demonstrate that the dRtf1 component of the Paf1 complex functions in Notch signaling.

Amino Acid Sequence↗
PubMed2006

Tax-dependent displacement of nucleosomes during transcriptional activation of human T-cell leukemia virus type 1.

The human T-cell leukemia virus type 1 (HTLV-1) is integrated into the host cell DNA and assembled into nucleosomes. Within the repressive chromatin environment, the virally encoded Tax protein mediates the recruitment of the coactivators CREB-binding protein/p300 to the HTLV-1 promoter, located within the long terminal repeats (LTRs) of the provirus. These proteins carry acetyltransferase activity that is essential for strong transcriptional activation of the virus in the context of chromatin. Consistent with this, the amino-terminal tails of nucleosomal histones at the viral promoter are acetylated in Tax-expressing cells. We have developed a system in which we transfect Tax into cells carrying integrated copies of the HTLV-1 LTR driving the luciferase gene to analyze changes in "activating" histone modifications at the LTR. Unexpectedly, Tax transactivation led to an apparent reduction of these modifications at the HTLV-1 promoter and downstream region that correlates with a similar reduction in histone H3 and linker histone H1. Micrococcal nuclease protection analysis showed that less LTR-luciferase DNA is nucleosomal in Tax-expressing cells. Furthermore, nucleosome depletion correlated with RNA polymerase II recruitment and loss of SWI/SNF. The M47 Tax mutant, deficient in HTLV-1 transcriptional activation, was also defective for nucleosome depletion. Although this mutant formed complexes with CREB and p300 at the HTLV-1 promoter in vivo, it was unable to mediate RNA polymerase II recruitment or SWI/SNF displacement. These results support a model in which nucleosomes are depleted from the LTR and transcribed region during Tax-mediated transcriptional activation and correlate RNA polymerase II recruitment with nucleosome depletion.

Animals↗
PubMed2003

Basal chromatin modification at the IL-4 gene in helper T cells.

Chromatin immunoprecipitations in naive CD4, but not CD8, T cells, demonstrated association of the IL-4 promoter with acetylated histone. Histone modifications and rapid IL-4 transcription were absent in conserved noncoding sequence 1 (CNS-1)(-/-) cells lacking an 8-kb-distant enhancer in the IL-4/IL-13 intergenic region, but also in CD4(-/-) and Itk(-/-) cells, which have similar Th2 deficiencies. Histones associated with the IL-13 promoter were not similarly acetylated in naive T cells, but became acetylated in differentiated Th2 cells. Conversely, Th1 differentiation induced histone methylation at the type 2 cytokine locus. Like CD4(-/-) and Itk(-/-) mice, CNS-1(-/-) BALB/c mice were highly resistant to the Th2-inducing protozoan, Leishmania major. CNS-1 deficiency led to failure of IL-4 gene repositioning to heterochromatin after Th1 polarization, possibly related to the presence of reiterative Ikaros binding sites in the intergenic element. Hyperacetylation of nonexpressed genes may serve to mark lineage-specific loci for rapid expression and further modification.

Animals↗
PubMed2003

Antigen receptor loci poised for V(D)J rearrangement are broadly associated with BRG1 and flanked by peaks of histone H3 dimethylated at lysine 4.

In the earliest stages of antigen receptor assembly, D and J segments of the Ig heavy chain and T cell receptor beta loci are recombined in B and T cells, respectively, whereas the V segments are not. Distinct distribution patterns of various histone modifications and the nucleosome-remodeling factor BRG1 are found at "active" (DJ) and "inactive" (V) regions. Striking "hotspots" of histone H3 dimethylated at lysine 4 (di-Me H3-K4) are localized at the ends of the active DJ domains of both the Ig heavy chain and T cell receptor beta loci. BRG1 is not localized to specific sequences, as it is with transcriptional initiation, but rather associates with the entire active locus in a pattern that mirrors acetylation of histone H3. Within some inactive loci marked by H3-K9 dimethylation, two distinct levels of methylation are found in a nonrandom gene-segment-specific pattern. We suggest that the hotspots of di-Me H3-K4 are important marks for locus accessibility. The specific patterns of modification imply that the regulation of V(D)J recombination involves recruitment of specific methyltransferases in a localized manner.

Animals↗
PubMed2005

Retrovirus silencing and vector design: relevance to normal and cancer stem cells?

An obstacle confronting gene therapy in stem cells is transcriptional silencing of the vector. Here, we discuss recent data indicating that oncoretrovirus and lentivirus vectors are silenced by multiple epigenetic pathways that result in DNA methylation and histone modifications. Both vector types can be variegated in stem cells and expression is often extinguished during differentiation. We propose a novel model of retrovirus silencing in which epigenetic pathways compete to recruit histone deacetylases, de novo methyltransferases, histone H1 and MeCP2 to the provirus. These chromatin modifications may act in concert with heterochromatin at or near the integration site to establish silencing or variegation respectively. Retrovirus vector designs for stem cells should delete virus silencer elements, incorporate strong positive regulatory elements and insulators, and avoid non-mammalian reporter genes. In addition, cancer stem cells that continually repopulate a growing tumour may share silencing pathways with normal stem cells. Ultimately, optimized vector designs may prove to be valuable tools for gene therapy of both normal and cancer stem cells.

Epigenesis, Genetic↗
PubMed2006

Developmental timing in Dictyostelium is regulated by the Set1 histone methyltransferase.

Histone-modifying enzymes have enormous potential as regulators of the large-scale changes in gene expression occurring during differentiation. It is unclear how different combinations of histone modification coordinate regimes of transcription during development. We show that different methylation states of lysine 4 of histone H3 (H3K4) mark distinct developmental phases of the simple eukaryote, Dictyostelium. We demonstrate that the enzyme responsible for all mono, di and tri-methylation of H3K4 is the Dictyostelium homolog of the Set1 histone methyltransferase. In the absence of Set1, cells display unusually rapid development, characterized by precocious aggregation of amoebae into multicellular aggregates. Early differentiation markers are abundantly expressed in growing set1 cells, indicating the differentiation program is ectopically activated during growth. This phenotype is caused specifically by the loss of Set1 catalytic activity. Set1 mutants induce premature differentiation in wild-type cells, indicating Set1 regulates production of an extra-cellular factor required for the correct perception of growth conditions. Microarray analysis of the set1 mutants reveals genomic clustering of mis-expressed genes, suggesting a requirement for Set1 in the regulation of chromatin-mediated events at gene clusters.

Amino Acid Sequence↗
PubMed2002

Cancer epigenomics.

Research in cancer epigenomics is driven by the development of novel technologies and the utilization of model organisms ranging from yeasts to plants to vertebrates. For decades, the search for cancer genes has focused on genetic defects that were used as tags for identification of these genes. With the realization that epigenetic modifications, most importantly DNA methylation events, are frequently involved in transcriptional changes in both tumor suppressor genes and oncogenes, techniques have been developed that support the identification of novel cancer genes altered by DNA methylation alone or in combination with genetic events. Recent data demonstrate that, in addition to DNA methylation, chromatin modifications are also involved in gene regulation. We are now beginning to understand this interesting interplay between chromatin modifications, DNA methylation and gene regulation. This review will summarize our current knowledge of DNA methylation and histone modification in normal cells, introduce emerging concepts that show the intimate link between DNA methylation and chromatin modifications, and highlight recent advancements in our understanding of aberrant DNA methylation, with special emphasis on genome-wide hypermethylation.

DNA Methylation↗
PubMed2005

Epigenetics of cervical cancer. An overview and therapeutic perspectives.

Cervical cancer remains one of the greatest killers of women worldwide. It is difficult to foresee a dramatic increase in cure rate even with the most optimal combination of cytotoxic drugs, surgery, and radiation; therefore, testing of molecular targeted therapies against this malignancy is highly desirable. A number of epigenetic alterations occur during all stages of cervical carcinogenesis in both human papillomavirus and host cellular genomes, which include global DNA hypomethylation, hypermetylation of key tumor suppressor genes, and histone modifications. The reversible nature of epigenetic changes constitutes a target for transcriptional therapies, namely DNA methylation and histone deacetylase inhibitors. To date, studies in patients with cervical cancer have demonstrated the feasibility of reactivating the expression of hypermethylated and silenced tumor suppressor genes as well as the hyperacetylating and inhibitory effect upon histone deacetylase activity in tumor tissues after treatment with demethylating and histone deacetylase inhibitors. In addition, detection of epigenetic changes in cytological smears, serum DNA, and peripheral blood are of potential interest for development of novel biomolecular markers for early detection, prediction of response, and prognosis.

Animals↗