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Posttranslational modifications of histones have been strongly correlated with transcriptional regulation. In this issue of Cell, comprehensively examined the nature of arginine methyltransferases and histone modifications in p53-mediated transcription.
Chromatin remodeling plays a key role in the transcriptional activation of regulatory factors in the liver in response to a variety of stress signals. The effects of burn injury on histone expression and its modification were investigated in this study. Liver tissues collected after a flame burn injury were subjected to RT-PCR and Western blot analyses of histone regulation. There was a marked induction of histone H3-D variant mRNA at 3 and 6 h. In contrast, histone H2A.2 variant mRNA had a downregulation at 3 days. No apparent changes were noted in other histone variants examined. Western blot analysis revealed a downregulation of all 5 histone subtypes (H1, H2A, H2B, H3, and H4) at 1 day and there was a subsequent induction of H1 and H2A subtypes at 3 days after injury. There was an induction of modified forms (phospho-, acetyl-, and dimethyl-) of histone H3 subtype at day 3. Furthermore, a transient elevation in PCNA (proliferating cell nuclear antigen) levels was apparent in the liver at day 3, which parallels the induction of phospho-histone H3, which is a mitosis marker. These findings suggest that histones participate in a cascade of events associated with phenotypic alterations in the liver after injury.
The posttranslational modification of histones by acetylation or methylation regulates chromatin structure and can determine how a DNA sequence is interpreted by, for example, the transcriptional machinery. In this issue of Cell, Pokholok and colleagues (2005) describe a new and reliable genome-wide microarray study of histone modifications and gene expression in yeast. Their epigenetic map can be used to guide further research on the epigenome.
Two antagonistic groups of genes, the trithorax- and the Polycomb-group, are proposed to maintain the appropriate active or inactive state of homeotic genes set up earlier by transiently expressed segmentation genes. Although some details about the mechanism of maintenance are available, it is still unclear how the initially active or inactive chromatin domains are recognized by either the trithorax-group or the Polycomb-group proteins. We describe an unusual dominant allele of a Polycomb-group gene, Enhancer of zeste, which mimics the phenotype of loss-of-function mutations in trithorax-group genes. This mutation, named E(z)(Trithorax mimic) [E(z)(Trm)], contains a single-amino-acid substitution in the conserved SET domain. The strong dominant trithorax-like phenotypes elicited by this E(z) allele suggest that the mutated arginine-741 plays a critical role in distinguishing between active and inactive chromatin domains of the homeotic gene complexes. We have examined the modification of E(z)(Trm) phenotypes by mutant alleles of PcG and trxG genes and other mutations that alter the phosphorylation of nuclear proteins, covalent modifications of histones, or histone dosage. These data implicate some trxG genes in transcriptional repression as well as activation and provide genetic evidence for involvement of histone modifications in PcG/trxG-dependent transcriptional regulation.
Quiescent lymphocytes have small nuclei, filled with masses of facultative heterochromatin. Upon receiving mitogenic signals, these cells undergo nuclear enlargement, chromatin decondensation, the reactivation of cell proliferation, and changes in the intranuclear positioning of key genes. We examined the levels and intranuclear localization of major histone modifications and non-histone heterochromatin proteins in quiescent and reactivated mouse spleen lymphocytes. Dramatic and selective changes in localization of two heterochromatin-associated proteins, the histone variant macroH2A and HP1alpha occurred during lymphocyte reactivation. Reciprocal changes in the locations of these two proteins were observed in activated lymphocytes and cultured mouse fibroblasts induced into quiescence. We also describe a new apocentric nuclear compartment with a unique set of histone modifications that occurs as a zone of chromatin surrounding centromeric heterochromatin in differentiated lymphocytes. It is within this zone that the most significant changes occur in the transition from proliferation to quiescence. Our results suggest that constitutive centromeric heterochromatin plays an active role in cell differentiation and reactivation.
Epigenetic factors alter phenotype without changing genotype. A primary molecular mechanism underlying epigenetics is the alteration of chromatin structure by covalent DNA modifications, covalent histone modifications, and nucleosome reorganization. Remodeling of chromatin structure regulates DNA methylation, replication, recombination, and repair as well as gene expression. As these functions would predict, dysfunction of the proteins that remodel chromatin causes an array of multi-system disorders and neoplasias. Insights from these diseases suggest that during embryonic and fetal life, environmental distortions of chromatin remodeling encode a 'molecular memory' that predispose the individual to diseases in adulthood.
Transcription activation of a gene involves the ordered recruitment of components of the basal transcription machinery in concert with alterations in chromatin structure, including nucleosome remodeling and post-translational modification of histones. Enhancers and locus control regions (LCRs) that are remote from the genes they activate, recruit the complexes that carry out these alterations and, sometimes, recruit RNA polymerase II. The question of how these distant activators interact with their target genes has been of long-standing interest. Recent data indicate that LCRs mediate contact with their coordinate genes through the formation of domains of histone modification and of intra- and inter-chromosomal loops and that they might localize genes within nuclear regions that favor transcription.
CpG island hypermethylation and global genomic hypomethylation are common epigenetic features of cancer cells. Less attention has been focused on histone modifications in cancer cells. We characterized post-translational modifications to histone H4 in a comprehensive panel of normal tissues, cancer cell lines and primary tumors. Using immunodetection, high-performance capillary electrophoresis and mass spectrometry, we found that cancer cells had a loss of monoacetylated and trimethylated forms of histone H4. These changes appeared early and accumulated during the tumorigenic process, as we showed in a mouse model of multistage skin carcinogenesis. The losses occurred predominantly at the acetylated Lys16 and trimethylated Lys20 residues of histone H4 and were associated with the hypomethylation of DNA repetitive sequences, a well-known characteristic of cancer cells. Our data suggest that the global loss of monoacetylation and trimethylation of histone H4 is a common hallmark of human tumor cells.
The regulation of gene expression via the histone code has, for the most part, revealed that histone modifications cause the recruitment of adaptor proteins that indirectly regulate the synthesis of RNA. Using purified factors to assemble and modify the chromatin and to transcribe the DNA, we investigated whether modifications of histones may directly impact the RNA polymerase II transcription process. We screened proteins known to modify histones for effects on transcription, and we found that the mitogen- and stress-induced kinase, MSK1, inhibited RNA synthesis. Inhibition of transcription by MSK1 was most sensitive when the template was in chromatin, as naked DNA templates were resistant to the effects of MSK1. We found that MSK1 phosphorylated histone H2A on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by MSK1. Furthermore, we found that acetylation of histone H3 by the p300 and CREB-binding protein associated factor, PCAF, suppressed the kinase-dependent inhibition of transcription. These results suggest that acetylation of histones may stimulate transcription by suppressing an inhibitory phosphorylation by a kinase as MSK1.
Replication of genomic material is a process that requires not only high fidelity in the duplication of DNA sequences but also inheritance of the chromatin states. In the last few years enormous effort has been put into elucidating the mechanisms involved in the correct propagation of chromatin states. From all these studies it emerges that an epigenetic network is at the base of this process. A coordinated interplay between histone modifications and histone variants, DNA methylation, RNA components, ATP-dependent chromatin remodeling, and histone-specific assembly factors regulates establishment of the replication timing program, initiation of replication, and propagation of chromatin domains. The aim of this review is to examine, in light of recent findings, how so many players can be coordinated with each other to achieve the same goal, a correct inheritance of the chromatin state.
The MLL gene breakpoint-cluster region (BCR) is a known hot-spot for chromosomal translocations in human leukemias. We mapped core histone modifications and histone H1 along the MLL gene in Jurkat cells and human CD34(+) progenitor blood cells by chromatin immunoprecipitation. Within the BCR, we found specific histone patterns that were different from other genomic regions and a histone H1-free fragment at the telomeric end. Core histone acetylase/deacetylase activities were also found within the BCR. In the studied cell models, chromatin components at the MLL BCR suggest an asymmetric organization that may influence early molecular events eventually leading to chromosomal translocations.
Immediate early genes (IEG) are rapidly but transiently induced directly by intracellular signaling cascades to alter patterns of gene expression. It has been proposed that histone modifications could be the key to the quick alteration of chromatin structure, as this spread occurs too rapidly to be the consequence of passage of RNA polymerase II. In this review, we will discuss the different modifications on histones and the chromatin remodeling enzymes, allowing the promoter regions of two IEGs, c-fos and c-jun, to be accessed.
In C. elegans, germline blastomeres are initially kept transcriptionally quiescent by the maternally loaded CCCH zinc-finger protein PIE-1. PIE-1 disappears upon the birth of the primordial germ cells Z2 and Z3, yet these cells appear to remain quiescent. We have previously demonstrated that there is a chromatin-based repression that succeeds PIE-1 degradation. The chromatin in Z2/Z3 loses certain histone modifications, including histone H3 lysine 4 dimethylation (H3K4me2), a conserved marker for transcriptionally competent chromatin. We find that mutations in the maternal-effect gene emb-4 cause defects in both PIE-1 degradation and germline-specific chromatin remodeling. emb-4 encodes a highly conserved protein with orthologs in fly, mouse, and human and has a subtle role in Notch signaling. The embryonic phenotype of emb-4 is consistent with a defect in the efficient and timely activation of developmental programs, including germline chromatin remodeling. We also find that, as in early somatic blastomeres, the degradation of PIE-1 in Z2/Z3 is facilitated by zinc-finger-interacting protein ZIF-1, and in the absence of either zif-1 or emb-4, PIE-1 is abnormally retained in Z2/Z3.
Covalent modifications of histones in active and bulk chromatin fractions were studied in liver tissue from control and hypothyroid rats. The levels of acetylation and ubiquitination of histones were similar in the active and bulk chromatin fractions, and were not influenced by hypothyroidism. Histone H2A only was phosphorylated in control active and bulk chromatin fractions. The extent of this phosphorylation did not differ between the two fractions, but hypothyroidism greatly suppressed it. Indicating an association with tissue growth. ADP-ribosylation of histones was found to be mainly associated with transcriptional inactivation of the chromatin, while histone methylation was correlated with growth inhibition of the tissue, as observed with hypothyroidism. The validity of these conclusions will, however, depend upon the similarity of the turnover rates of these covalent modifications between active and inactive chromatin and between control and hypothyroid states.
The human ISWI-containing factor RSF (remodeling and spacing factor) was found to mediate nucleosome deposition and, in the presence of ATP, generate regularly spaced nucleosome arrays. Using this system, recombinant chromatin was reconstituted with bacterially produced histones. Acetylation of the histone tails was found to play an important role in establishing regularly spaced nucleosome arrays. Recombinant chromatin lacking histone acetylation was impaired in directing transcription. Histone-tail modifications were found to regulate transcription from the recombinant chromatin. Acetylation of the histone tails by p300 was found to increase transcription. Methylation of the histone H3 tail by Suv39H1 was found to repress transcription in an HP1-dependent manner. The effects of histone-tail modifications were observed in nuclear extracts. A highly reconstituted RNA polymerase II transcription system was refractory to the effect imposed by acetylation and methylation.
A relationship between side-chain modification of histones and their displaceability from DNA has been investigated using calf thymus chromatin which was chemically acetylated with acetic anhydride. When the chromatin is treated with increasingly higher concentrations of the reagent, histones become acetylated to an increasingly greater extent, attaining the modification at 23-24 sites for histone I, 5-6 for IIb1, 9-10 for IIb2, 5-6 for III and 3-4 for IV. As the chromatin becomes more acetylated, NaCl concentrations required for histone removal are lowered. Saturation binding of protamine does not bring about either an increase in the number of acetylation sites of histones in chromatin or a decrease of the NaCl requirement for dissociation of the acetylated chromatins. A comparison of the present results with the extents of histone acetylation known to occur enzymatically in vivo indicates that the complete removal of somatic histones during transformation of chromatin in spermiogenesis cannot be explained on the basis of decreased binding of the histone to DNA by acetylation or by a combination of acetylation and protamine binding, suggesting that the displacement process may require some additional processes.
The anti-cancer drug cisplatin kills cells by damaging DNA and inducing apoptosis. Understanding the detailed mechanisms by which cancer cells respond to cisplatin has the potential to improve substantially platinum-based therapy. Post-translational modification of histones alters chromatin structure, facilitating the binding of nuclear factors that mediate DNA repair, transcription, and other processes. In the present study, we have investigated the effects of cisplatin treatment on histone post-translational modification in cancer cells. We discovered that specific phosphorylation of histone H3 at Ser-10, mediated by the p38 MAPK pathway, is induced in response to cisplatin treatment. In addition, hyperacetylation of histone H4 was caused by drug treatment. These findings revealed a link between cisplatin administration and chromosomal structural alterations, providing mechanistic information about how cells respond to platinum-induced stress.
A novel histone methyltransferase, termed Set9, was isolated from human cells. Set9 contains a SET domain, but lacks the pre- and post-SET domains. Set9 methylates specifically lysine 4 (K4) of histone H3 (H3-K4) and potentiates transcription activation. The histone H3 tail interacts specifically with the histone deacetylase NuRD complex. Methylation of histone H3-K4 by Set9 precludes the association of NuRD with the H3 tail. Moreover, methylation of H3-K4 impairs Suv39h1-mediated methylation at K9 of H3 (H3-K9). The interplay between the Set9 and Suv39h1 histone methyltransferases is specific, as the methylation of H3-K9 by the histone methyltransferase G9a was not affected by Set9 methylation of H3-K4. Our studies suggest that Set9-mediated methylation of H3-K4 functions in transcription activation by competing with histone deacetylases and by precluding H3-K9 methylation by Suv39h1. Our results suggest that the methylation of histone tails can have distinct effects on transcription, depending on its chromosomal location, the combination of posttranslational modifications, and the enzyme (or protein complex) involved in the particular modification.