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PubMedDate not supplied

Chromatin remodeling and cancer.

The fate of the cell relies on a delicate balance between gene expression and repression. The transcriptional control of the genome is maintained not only by transcription factors but also chromatin remodeling proteins. The purpose of the chromatin remodeling proteins is to alter the nucleosome architecture such that genes are exposed to or hidden from the transcriptional machinery. The nucleosome can be restructured by two mechanisms: 1. the movement of nucleosomes along DMA which is carried out by ATP-dependent chromatin remodeling complexes; and 2. the modification of core histones by histone acetyltransferases, deactylases, methyltrans-ferases, and kinases. Since these chromatin remodeling proteins play an essential role in transcriptional regulation, it is not surprising that they have been linked to cancer. In this review, we provide a general overview on chromatin remodeling and describe known genetic alterations of chromatin remodeling proteins in human cancers. We also discuss potential other, as yet unexplored strategies that cancers might take to manipulate the chromatin remodeling machinery.

Acetylation↗
PubMed2004

Understanding the consequences of epigenetic mechanisms and its effects on transcription in health and disease.

Over the course of thirty-five years of research into the chromosome we are confronted with a number of general conclusions central to chromatin biology, perhaps most pertinent of these is that organization of higher order nucleosome structures play a fundamental role in DNA behavior. Folding and packaging of DNA is linked with a number of processes ranging from transcriptional regulation, genome stability, chromosome segregation, including replication and repair. Intrinsic to nuclear function is chromatin structure and the relationship with epigenetic modification. While we are aware that genetic and epigenetic changes can influence tumorigenesis, it is still unclear what protein components are specified on chromatin or the molecular events that underlie the link between chromosomes and cancer. In recent years, our understanding of DNA methylation with cancer development has revealed some surprising findings with particular emphasis on the antithetical character of hypo- and hyper- methylation of DNA. The molecular mechanism by which methylation is responsible for increased cancer risk has received widespread attention and is relavent to our understanding of genetic stability. The biological significance of other epigenetic modifications such as histone tail changes and active chromatin remodeling are also a major driving force in chromosome research in cancer. In light of recent advances in the understanding of epigenetic changes in disease we have organized a focused review series and discuss the significance of Epigenetics in Normal Control and Deregulation in Cancer. Authors from divergent fields of study have contributed articles that examine chromatin dynamics in cancer, bringing together research interests from a wide variety of fields. In this vein, we discuss the consequences of deregulating epigenetic mechanisms with a viewpoint on transcriptional control, chromatin function and human disease.

Chromatin↗
PubMed2006

Estimating the prevalence and regulatory potential of the telomere looping effect in yeast transcription regulation.

Telomeres have long been implicated in the regulation of gene expression. Some studies have reported that telomere looping effect (TLE) can juxtapose genes and regulatory sequences that are far apart and facilitate long-distance control of gene expression. In this work, we report a detailed investigation on the prevalence and regulatory potential of TLE on a genomic scale by assembling data on protein-DNA interactions from several large-scale ChIp-chip experiments in Saccharomyces cerevisiae. Analysis of the assembled data revealed that a statistically significant number of DNA segments that were inferred to be bound by ten or more transcription factors in these experiments physically mapped to the ends of several chromosomes (19 of 32 chromosome ends). For the 83 transcription factors that were inferred to interact with these DNA segments, we found a statistically significant skew in the distribution of their internal binding sites over the length of the entire chromosome, such that more than expected binding events occurred proximal to chromosomal ends than elsewhere. Taken together these observations suggest that the telomere looping effect is their most likely explanation and imply that a notable fraction of the internally bound yeast transcription factors potentially interact with looped back telomeres. Further, we also identified several components of the basal transcriptional machinery that are also frequently linked to these chromosome end segments, strengthening the proposal for a direct interaction between the chromosome ends and internally located transcriptional complexes. We observed that certain chromatin factors might participate in the TLE and potentially modulate gene expression by chromatin modifications such as histone deacetylation. Our findings provide the first computational evidence for a significant role of long-range regulatory interactions due to telomere looping. Based on these observations, we also propose that genome-wide chromatin immunoprecipitation data might be useful to systematically uncover long-range chromatin looping effects in gene expression.

Binding Sites↗
PubMedDate not supplied

[Features of the process of chromatin denaturation in leukemic tissue and murine spleen cells].

It was shown by the method of differential scanning microcalorimetry that an additional peak, at about 57 degrees C appears on heat absorption curves of the whole spleen tissue and cells of BalB/c mouse injected with Rausher virus. It is supposed that this peak is due to the melting of AT-rich regions of internucleosomal DNA in chromatin fibers of tumor cells, which results from the partial loss of proteins or the modification of H1 histone.

AT Rich Sequence↗
PubMed2006

[Epigenetics and cancer].

The term epigenetics encompasses all the modifications that are stable across cell generations, but which do not imply any change in DNA sequence. Post-translational modifications of the histones and DNA methylation are the most studied types of epigenetic information due to their major impact on transcription. The link between epigenetics and cancer arises from the fact that epigenetic deregulations frequently participate in tumorigenesis by inactivation of tumour-suppressor genes. Since these deregulations are reversible, hopes of treatment rely on a better understanding of the maintenance mechanisms of the epigenetic information. Among the different pathways of transcription inhibition, DNA methylation is the simplest and one of the best characterized at the present time. Inhibitors of DNA methyltransferases are currently under clinical trials and already show promising results.

DNA Methylation↗
PubMed2005

Imprinting centers, chromatin structure, and disease.

Two regions that best exemplify the role of genetic imprinting in human disease are the Prader-Willi syndrome/Angelman syndrome (PWS/AS) region in 15q11-q13 and the Beckwith-Wiedemann syndrome (BWS) region in 11p15.5. In both regions, cis-acting sequences known as imprinting centers (ICs) regulate parent-specific gene expression bidirectionally over long distances. ICs for both regions are subject to parent-specific epigenetic marking by covalent modification of DNA and histones. In this review, we summarize our current understanding of IC function and IC modification in these two regions.

Chromatin↗
PubMed2000

Synergistic coupling of histone H3 phosphorylation and acetylation in response to epidermal growth factor stimulation.

Histone acetylation and phosphorylation have separately been suggested to affect chromatin structure and gene expression. Here we report that these two modifications are synergistic. Stimulation of mammalian cells by epidermal growth factor (EGF) results in rapid and sequential phosphorylation and acetylation of H3, and these dimodified H3 molecules are preferentially associated with the EGF-activated c-fos promoter in a MAP kinase-dependent manner. In addition, the prototypical histone acetyltransferase Gcn5 displays an up to 10-fold preference for phosphorylated (Ser-10) H3 over nonphosphorylated H3 as substrate in vitro, suggesting that H3 phosphorylation can affect the efficiency of subsequent acetylation reactions. Together, these results illustrate how the addition of multiple histone modifications may be coupled during the process of gene expression.

Acetylation↗
PubMed2000

Acetylation: a regulatory modification to rival phosphorylation?

The fact that histones are modified by acetylation has been known for almost 30 years. The recent identification of enzymes that regulate histone acetylation has revealed a broader use of this modification than was suspected previously. Acetylases are now known to modify a variety of proteins, including transcription factors, nuclear import factors and alpha-tubulin. Acetylation regulates many diverse functions, including DNA recognition, protein-protein interaction and protein stability. There is even a conserved structure, the bromodomain, that recognizes acetylated residues and may serve as a signalling domain. If you think all this sounds familiar, it should be. These are features characteristic of kinases. So, is acetylation a modification analogous to phosphorylation? This review sets out what we know about the broader substrate specificity and regulation of acetyl- ases and goes on to compare acetylation with the process of phosphorylation.

Acetylation↗
PubMed2002

Phosphorylation of histone H3 is functionally linked to retinoic acid receptor beta promoter activation.

Ligand-dependent transcriptional activation of retinoic acid receptors (RARs) is a multistep process culminating in the formation of a multimeric co-activator complex on regulated promoters. Several co-activator complexes harbor an acetyl transferase activity, which is required for retinoid-induced transcription of reporter genes. Using murine P19 embryonal carcinoma cells, we examined the relationship between histone post-translational modifications and activation of the endogenous RARbeta2 promoter, which is under the control of a canonical retinoic acid response element and rapidly induced upon retinoid treatment. While histones H3 and H4 were constitutively acetylated at this promoter, retinoid agonists induced a rapid phosphorylation at Ser10 of histone H3. A retinoid antagonist, whose activity was independent of co-repressor binding to RAR, could oppose this agonist-induced H3 phosphorylation. Since such post-translational modifications were not observed at several other promoters, we conclude that histone H3 phosphorylation may be a molecular signature of the activated, retinoid-controlled mRARbeta2 gene promoter.

Animals↗
PubMed2025

Dynamic association of H3K36me3 with pericentromeric heterochromatin regulates its replication time.

The flexibility of the spatio-temporal genome replication program during development and disease highlights the regulatory role of plastic epigenetic mechanisms over genetic determinants. Histone post-translational modifications are broadly implicated in replication timing control, yet the specific mechanisms through which individual histone marks influence replication dynamics, particularly in heterochromatin, remain unclear. Here, we demonstrate that H3K36me3 dynamically enriches at pericentromeric heterochromatin, composed of major satellite DNA repeats, prior to replication during mid S phase in mouse embryonic stem cells. By knocking down lysine 36-specific methyltransferases or by targeting the H3K36M oncohistone to pericentromeric heterochromatin, we reduce global or local H3K36me3 levels, respectively, revealing its essential role in preserving the replication timing of constitutive heterochromatin. Loss of H3K36me3 accompanies increased RNA polymerase II serine-5 phosphorylation and lowered major satellite RNA levels, indicating transcriptional dysregulation. Notably, we identify a strand-specific contribution of major satellite forward transcripts in regulating the replication timing of constitutive heterochromatin and maintaining chromatin stability, highlighting the importance of non-coding RNAs as critical regulators of replication timing.

Heterochromatin↗
PubMed2000

Phosphorylation of serine 10 in histone H3 is functionally linked in vitro and in vivo to Gcn5-mediated acetylation at lysine 14.

Multiple covalent modifications exist in the amino-terminal tails of core histones, but whether a relationship exists between them is unknown. We examined the relationship between serine 10 phosphorylation and lysine 14 acetylation in histone H3 and have found that, in vitro, several HAT enzymes displayed increased activity on H3 peptides bearing phospho-Ser-10. This augmenting effect of Ser-10 phosphorylation on acetylation by yGcn5 was lost by substitution of alanine for arginine 164 [Gcn5(R164A)], a residue close to Ser-10 in the structure of the ternary tGcn5/CoA/histone H3 complex. Gcn5(R164A) had reduced activity in vivo at a subset of Gcn5-dependent promoters, and, strikingly, transcription of this same subset of genes was also impaired by substitution of serine 10 to alanine in the histone H3 tail. These observations suggest that transcriptional regulation occurs by multiple mechanistically linked covalent modifications of histones.

Acetylation↗
PubMed1999

Chromatin modification: how to put a HAT on the histones.

Specific patterns of acetylation of the core histones are associated with specific structures and functions of chromatin. A basis for the specificity of acetylation is now apparent in the recent crystal structures of two acetyltransferases.

Acetylation↗
PubMed1995

Relationship between methylation and acetylation of arginine-rich histones in cycling and arrested HeLa cells.

In the following report the relationship between histone methylation and histone acetylation has been examined in HeLa cells to better define the distribution of these two modifications. By labeling methylated histones in the presence or absence of sodium butyrate, we have found that the methylation of H3 is much more targeted to rapidly acetylated chromatin than is the methylation of H4, which largely involves the unacetylated subtype even in the presence of butyrate. Newly methylated H3 is highly likely to be complexed in nucleosomes that contain acetylated H4, as determined by immunoprecipitating radiolabeled chromatin with antibodies specific for acetylated H4 isoforms. In contrast, dynamically methylated H4 is underrepresented in acetylated chromatin, relative to newly methylated H3. The preferential methylation of acetylated H3 continues after pretreatment of cells with cycloheximide, indicating that not all acetylation-related methylation is associated with histone synthesis. This was confirmed by analyzing histone methylation in cells arrested at the G1/S boundary, in which histone synthesis was sharply lowered (relative to randomly cycling cells): under these conditions H3 methylation declined only approximately 4-fold, although ongoing methylation of H4 decreased approximately 20-fold. The continuing methylation of H3 in arrested cells included all H3 sequence variants, was selective for acetylated H3, and coincided with methyl group turnover that could not be ascribed to histone replacement synthesis. Most newly methylated H3 in arrested cells was complexed with acetylated H4 in chromatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMed1979

[Immunochemical analysis of histone H1 and H5 from pigeon erythroid cells].

An antiserum with the antibody titer of 1 : 4096 was obtained by immunization of rabbits with the tRNA-histone H5 complex from pigeon erythrocytes. The specificity of the antiserum was studied quantitatively from the reaction of the complement binding to a homologous antigen (histone H5) and its modifications (I, II, III), differing in the degree of phosphorylation. It was shown that phosphorylation of histone H5 increases the ability of the antigen to bind to antibodies, which is especially well-pronounced at the antiserum dilutions as high as 20480. The comparison of the antigenic properties of histones H5 from pigeon and chicken erythrocytes revealed beside structural differences of the proteins the presence of common antigenic determinants. A similar observation was made when histones H5 and H1 from pigeon erythrocytes were compared. Histone H1 from chicken erythrocytes and histone H1 from calf thymus did not produce criss-cross reactions with antiserum H5.

Animals↗
PubMed2005

Histone H3 phosphorylation can promote TBP recruitment through distinct promoter-specific mechanisms.

Histone phosphorylation influences transcription, chromosome condensation, DNA repair and apoptosis. Previously, we showed that histone H3 Ser10 phosphorylation (pSer10) by the yeast Snf1 kinase regulates INO1 gene activation in part via Gcn5/SAGA complex-mediated Lys14 acetylation (acLys14). How such chromatin modification patterns develop is largely unexplored. Here we examine the mechanisms surrounding pSer10 at INO1, and at GAL1, which herein is identified as a new regulatory target of Snf1/pSer10. Snf1 behaves as a classic coactivator in its recruitment by DNA-bound activators, and in its role in modifying histones and recruiting TATA-binding protein (TBP). However, one important difference in Snf1 function in vivo at these promoters is that SAGA recruitment at INO1 requires histone phosphorylation via Snf1, whereas at GAL1, SAGA recruitment is independent of histone phosphorylation. In addition, the GAL1 activator physically interacts with both Snf1 and SAGA, whereas the INO1 activator interacts only with Snf1. Thus, at INO1, pSer10's role in recruiting SAGA may substitute for recruitment by DNA-bound activator. Our results emphasize that histone modifications share general functions between promoters, but also acquire distinct roles tailored for promoter-specific requirements.

Biological Transport, Active↗
PubMed2004

Understanding global changes in histone H1 phosphorylation using mass spectrometry.

Histone post-translational modifications have been implicated in a variety of biological processes such as gene expression, DNA replication, and chromatin assembly. The modifications include methylation, acetylation, phosphorylation, ubiquitination, glycosylation, and ADP-ribosylation. For several years, we have been investigating the role of histone H1 phosphorylation in transcription using the hormone inducible mouse mammary tumor virus (MMTV) promoter. When mouse cells were exposed to prolonged treatment with dexamethasone, a significant decrease in the level of histone H1 phosphorylation was observed. Traditionally, Western analyses with anti-histone H1 and phospho-specific H1 antibodies were performed to observe changes in phosphorylation levels of the bulk H1 histones. More recently, we have applied electrospray ionization mass spectrometry to the analysis of histone H1 isoforms. Utilizing this approach, we have investigated the phosphorylation state of the specific H1 isoforms before and after prolonged treatment with dexamethasone. Specifically, we could determine that the relative phosphorylation levels of the histone H1.3, H1.4, and H1.5 isoforms decrease after prolonged hormone exposure. Recent advancements in mass spectrometry have proven invaluable toward the analysis of post-translational modifications on proteins. The continued developments in the area of mass spectrometry should provide new insights into not only the function of proteins but also into the basic regulatory mechanisms that control cellular functions.

Animals↗