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PubMed2004

Epigenetics in human disease and prospects for epigenetic therapy.

Epigenetic mechanisms, which involve DNA and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. The study of human disease has focused on genetic mechanisms, but disruption of the balance of epigenetic networks can cause several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. Great potential lies in the development of 'epigenetic therapies'--several inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone deacetylases, have shown promising anti-tumorigenic effects for some malignancies.

DNA Methylation↗
PubMed2005

Histone-modifying complexes regulate gene expression pertinent to the differentiation of the protozoan parasite Toxoplasma gondii.

Pathogenic apicomplexan parasites like Toxoplasma and Plasmodium (malaria) have complex life cycles consisting of multiple stages. The ability to differentiate from one stage to another requires dramatic transcriptional changes, yet there is a paucity of transcription factors in these protozoa. In contrast, we show here that Toxoplasma possesses extensive chromatin remodeling machinery that modulates gene expression relevant to differentiation. We find that, as in other eukaryotes, histone acetylation and arginine methylation are marks of gene activation in Toxoplasma. We have identified mediators of these histone modifications, as well as a histone deacetylase (HDAC), and correlate their presence at target promoters in a stage-specific manner. We purified the first HDAC complex from apicomplexans, which contains novel components in addition to others previously reported in eukaryotes. A Toxoplasma orthologue of the arginine methyltransferase CARM1 appears to work in concert with the acetylase TgGCN5, which exhibits an unusual bias for H3 [K18] in vitro. Inhibition of TgCARM1 induces differentiation, showing that the parasite life cycle can be manipulated by interfering with epigenetic machinery. This may lead to new approaches for therapy against protozoal diseases and highlights Toxoplasma as an informative model to study the evolution of epigenetics in eukaryotic cells.

Acetylation↗
PubMed2007

Gene regulation by chromatin structure: paradigms established in Drosophila melanogaster.

Studies in Drosophila melanogaster have revealed paradigms for regulating gene expression through chromatin structure, including mechanisms of gene activation and silencing. Regulation occurs at the level of individual genes, chromosomal domains, and entire chromosomes. The chromatin state is dynamic, allowing for changes in gene expression in response to cellular signals and/or environmental cues. Changes in chromatin result from the action of ATP-dependent chromatin-remodeling complexes, reversible epigenetic histone modifications, and the incorporation of histone variants. Many of the chromatin-based transcriptional regulatory mechanisms discovered in D. melanogaster are evolutionarily conserved and therefore serve as a foundation for studies in other organisms.

Adenosine Triphosphatases↗
PubMed2006

[Research advances on the relationship of PI3-kinase/Akt/mTOR pathway and epigenetic modification].

The mammalian target of rapamycin (mTOR) has been shown to link growth factor signaling and posttranscriptional control of protein translation through activation of the PI3K/Akt pathway, which is frequently involved in cell cycle progression. The inhibition of mTOR has promising potential in anticancer and immunosuppressive therapies, and additional phase II clinical trials are ongoing. Epigenetic modification, which involves DNA methylation, histone modification and chromatin remodeling, as well as the recently described RNAi mechanism, can initiate the formation of silenced chromatin. Persistent activation or inhibition of the mTOR pathway may affect epigenetic modification. In this paper, we reviewed the research advances in the relationship between PI3K/Akt/mTOR and epigenetic modification.

Animals↗
PubMed2026

Somatic genetic alterations in pituitary neuroendocrine tumors.

The molecular characterization of pituitary neuroendocrine tumors (PitNETs) has progressed pronouncedly in recent years, unraveling the molecular pathways driving initiation and progression of different PitNET types and allowing a better understanding of their biology. The most frequent recurring somatic driver alterations were recognized in corticotroph PitNETs (USP8, USP48, BRAF) and somatotroph PitNETs (GNAS) and, much less frequently, in lactotroph PitNETs (SF3B1). Additional well-characterized somatic driver alterations, including TP53, ATRX, and DAXX, are enriched in aggressive corticotroph tumors. Identification of new molecular markers and delineation of their clinical phenotypes are enabling further subclassification of PitNETs based on tumor molecular profiles, with earlier recognition of more aggressive variants. These molecular markers also provide an opportunity for new targeted therapies. Beyond single-gene alterations, epigenetic modifications, such as DNA methylation, histone modifications, and noncoding RNA dysregulation, are emerging as important contributors to PitNET pathogenesis and potential therapeutic targets. Multi-omics approaches encompassing genomics, transcriptomics, epigenomics, and proteomics are transforming PitNET classification. In this review, we provide a comprehensive, data-driven update on somatic driver alterations, epigenetic alterations, converging signaling pathways, and the related emerging therapeutic targets in PitNETs, integrating pooled analyses from published cohorts.

Humans↗
PubMed2006

The tale beyond the tail: histone core domain modifications and the regulation of chromatin structure.

Histone post-translational modifications occur, not only in the N-terminal tail domains, but also in the core domains. While modifications in the N-terminal tail function largely through the regulation of the binding of non-histone proteins to chromatin, based on their location in the nucleosome, core domain modifications may also function through distinct mechanisms involving structural alterations to the nucleosome. This article reviews the recent developments in regards to these novel histone modifications and discusses their important role in the regulation of chromatin structure.

Animals↗
PubMed2004

Reversal of gene silencing as a therapeutic target for cancer--roles for DNA methylation and its interdigitation with chromatin.

It has become apparent over the past several years that one of the attractive emerging prevention and therapy targets for cancer is the reversal of aberrant gene silencing mediated by epigenetic events associated with transcriptional repression. Integral to the possibilities for this targeting is the need to dissect the molecular mechanisms which underlie these transcriptional changes. At present, the best studied of the epigenetically silenced genes involved in cancer are those which harbour aberrant DNA promoter region methylation. This growing list includes almost half of all proven tumour suppressor genes and also a rapidly expanding list of genes with candidate roles for antitumour activities as well. Thus, one approach receiving much attention for restoring expression of abnormally silenced cancer genes for therapeutic purposes is utilization of agents such as 5-azacytidine (5-AzaC) and 5'-deoxy-azacytidine (DAC), which inhibit the DNA methyltransferases (DNMTs) that catalyse DNA methylation. Other approaches, and particularly the notion of utilizing inhibitors of histone de-acetylation, are being suggested by the exploding body of data concerning the role of histone modifications in mediating gene expression status, and especially those parameters that participate in gene silencing. Importantly, these histone parameters, which are the focus of this Novartis Foundation Symposium, are not only tightly linked to mechanisms through which DNA methylation participates in gene silencing, but are also being integrally linked to how abnormal patterns of this DNA modification may actually arise in tumour cells. In this brief review, it is hypothesized that these interactions between DNA methylation and histone modifications may have to be targeted to most effectively exploit the potential for using reversal of gene silencing as an approach to cancer prevention and treatment.

Animals↗
PubMed2004

Modulation of heat shock gene expression by the TAC1 chromatin-modifying complex.

Rapid induction of the Drosophila melanogaster heat shock gene hsp70 is achieved through the binding of heat shock factor (HSF) to heat shock elements (HSEs) located upstream of the transcription start site (reviewed in ref. 3). The subsequent recruitment of several other factors, including Spt5, Spt6 and FACT, is believed to facilitate Pol II elongation through nucleosomes downstream of the start site. Here, we report a novel mechanism of heat shock gene regulation that involves modifications of nucleosomes by the TAC1 histone modification complex. After heat stress, TAC1 is recruited to several heat shock gene loci, where its components are required for high levels of gene expression. Recruitment of TAC1 to the 5'-coding region of hsp70 seems to involve the elongating Pol II complex. TAC1 has both histone H3 Lys 4-specific (H3-K4) methyltransferase (HMTase) activity and histone acetyltransferase activity through Trithorax (Trx) and CREB-binding protein (CBP), respectively. Consistently, TAC1 is required for methylation and acetylation of nucleosomal histones in the 5'-coding region of hsp70 after induction, suggesting an unexpected role for TAC1 during transcriptional elongation.

Animals↗
PubMed2005

Epigenetic changes in solid and hematopoietic tumors.

There are three connected molecular mechanisms of epigenetic cellular memory in mammalian cells: DNA methylation, histone modifications, and RNA interference. The first two have now been firmly linked to neoplastic transformation. Hypermethylation of CpG-rich promoters triggers local histone code modifications resulting in a cellular camouflage mechanism that sequesters gene promoters away from transcription factors and results in stable silencing. This normally restricted mechanism is ubiquitously used in cancer to silence hundreds of genes, among which some critically contribute to the neoplastic phenotype. Virtually every pathway important to cancer formation is affected by this process. Methylation profiling of human cancers reveals tissue-specific epigenetic signatures, as well as tumor-specific signatures, reflecting in particular the presence of epigenetic instability in a subset of cancers affected by the CpG island methylator phenotype. Generally, methylation patterns can be traced to a tissue-specific, proliferation-dependent accumulation of aberrant promoter methylation in aging tissues, a process that can be accelerated by chronic inflammation and less well-defined mechanisms including, possibly, diet and genetic predisposition. The epigenetic machinery can also be altered in cancer by specific lesions in epigenetic effector genes, or by aberrant recruitment of these genes by mutant transcription factors and coactivators. Epigenetic patterns are proving clinically useful in human oncology via risk assessment, early detection, and prognostic classification. Pharmacologic manipulation of these patterns-epigenetic therapy-is also poised to change the way we treat cancer in the clinic.

Alleles↗
PubMed2005

Epigenetic reprogramming throughout preimplantation development and consequences for assisted reproductive technologies.

Knowledge about preimplantation development is important both for basic reproductive biology and for practical applications, including livestock breeding and regenerative medicine. During preimplantation development, epigenetic modifications such as DNA methylation and histone modifications are involved in the regulation of imprinted and non-imprinted genes, in the initiation of X chromosome inactivation, and the adjustment of telomere length. The underlying events are particularly vulnerable to external factors. Characterization of expression profiles in in vivo-derived embryos of different developmental stages and understanding the mechanisms and dynamics underlying the reprogramming process are the first steps towards the analysis of the complex gene regulatory networks. They provide a baseline for the analysis of manipulated embryos of all mammalian species, including humans, to improve embryo technologies and related therapeutic applications.

Animals↗
PubMed1997

Biochemical analysis of chromatin structure and function using Drosophila embryo extracts.

The biochemical analysis of chromatin structure and function is greatly facilitated by the availability of cell-free systems that assemble chromatin under physiological conditions. One such system that has shown great potential is derived from extracts of early Drosophila embryos. These embryos contain large maternal stocks of chromatin constituents, such as histones and assembly factors. Chromatin assembled in these extracts resembles native chromatin in many respects: it displays physiological nucleosome repeat lengths, it is complex, containing a wealth of nonhistone proteins as well as enzymatic activities, and it has dynamic properties that allow the interaction of DNA-binding proteins that regulate important cellular processes. Most importantly, chromatin with variant properties, e.g., with respect to the basic geometry of the nucleosomal array, histone modifications, and its content of linker histones or nonhistone proteins, can be obtained by manipulating the reconstitution conditions. The synthesis of uniform chromatin with specific characteristics should allow the analysis of the functional significance of the structural and biochemical heterogeneity observed in vivo.

Animals↗
PubMed1987

Phenotypes of HeLa S3 variant cell lines resistant to growth inhibition by sodium butyrate.

HeLa cell variants capable of multiplying in the presence of sodium butyrate were used to study the relationship of cell cycle position to human chorionic gonadotropin (hCG) production and regulation of the genes encoding hCG alpha- and beta-subunits. The butyrate-resistant variants exhibit several different stable phenotypes. In wild-type HeLa cells, butyrate arrests cell division and modulates synthesis of alpha- and beta-subunits of glycoprotein hormones by coordinately regulating steady-state levels of their respective mRNAs. Because the variant cell lines replicate, in addition to producing hCG subunits in the presence of butyrate, cell cycle arrest does not seem to be a requirement for expression of glycoprotein hormone genes. Studies of histone modification suggest that neither hyperacetylation of histones H3 and H4 nor dephosphorylation of histones H1 and H2A mediates inhibition of cell replication. In the variants, alpha-subunit and hCG beta levels are independently regulated, as a consequence of independent regulation of alpha- and beta-hCG mRNA levels. Long-term effects of butyrate include derepression of some genes (hCG beta in the variant AO) and repression of others (hCG alpha in variant AO). Moreover, hormone production correlates with the steady-state levels of mRNA for each of the subunits, suggesting that regulation occurs before translation. These findings indicate that the butyrate-resistant variant cell lines are valuable for studies of the molecular mechanisms involved in regulation of expression of ectopic hormones.

Acetylation↗
PubMed2005

GMP synthetase stimulates histone H2B deubiquitylation by the epigenetic silencer USP7.

The packaging of eukaryotic genomic DNA into chromatin is modulated through a range of posttranslational histone modifications. Among these, the role of histone ubiquitylation remains poorly understood. Here, we show that the essential Drosophila ubiquitin-specific protease 7 (USP7) contributes to epigenetic silencing of homeotic genes by Polycomb (Pc). We purified USP7 from embryo nuclear extracts as a stable heteromeric complex with guanosine 5'-monophosphate synthetase (GMPS). The USP7-GMPS complex catalyzed the selective deubiquitylation of histone H2B, but not H2A. Biochemical assays confirmed the tight association between USP7 and GMPS in Drosophila embryo extracts. Similar to USP7, mutations in GMPS acted as enhancers of Pc in vivo. USP7 binding to GMPS was required for histone H2B deubiquitylation and strongly augmented deubiquitylation of the human tumor suppressor p53. Thus, GMPS can regulate the activity of a ubiquitin protease. Collectively, these results implicate a biosynthetic enzyme in chromatin control via ubiquitin regulation.

Animals↗
PubMed1998

The nucleosome: a powerful regulator of transcription.

Nucleosomes provide the architectural framework for transcription. Histones, DNA elements, and transcription factors are organized into precise regulatory complexes. Positioned nucleosomes can facilitate or impede the transcription process. These structures are dynamic, reflecting the capacity of chromatin to adopt different functional states. Histones are mobile with respect to DNA sequence. Individual histone domains are targeted for posttranslational modifications. Histone acetylation promotes transcription factor access to nucleosomal DNA and relieves inhibitory effects on transcriptional initiation and elongation. The nucleosomal infrastructure emerges as powerful contributor to the regulation of gene activity.

Animals↗
PubMed2006

Targeting an E2F site in the mouse genome prevents promoter silencing in quiescent and post-mitotic cells.

Previous studies have shown that the cell cycle-regulated B-myb promoter contains a conserved E2F binding site that is critical for repressing transcription in quiescent cells. To investigate its significance for permanent promoter silencing, we have inactivated this binding site in the mouse genome. Mice homozygous for the mutant B-mybmE2F allele were fully viable, however, B-myb transcription was derepressed during quiescence in mouse embryo fibroblasts (MEFs) derived from mutant animals. Moreover, it was found that mutation of the E2F site resulted in abnormal maintenance of B-myb expression in senescent MEFs and in differentiated brain tissue. These findings therefore reveal a direct and primary role for repressive E2F complexes in silencing gene expression in post-mitotic cells. Analysis of histone modifications at the promoter showed that histone H3 lysine 9 was constitutively acetylated throughout the cell cycle in homozygous mutant MEFs. This mouse system is the first description of an E2F site mutation in situ and will facilitate the study of E2F function in vivo.

Animals↗
PubMed2005

Messenger RNA expression patterns in bovine embryos derived from in vitro procedures and their implications for development.

The preimplantation bovine embryo is initially under the control of maternal genomic information that is accumulated during oogenesis. The genetic programme of development soon becomes dependent on new transcripts derived from activation of the embryonic genome. The early steps in development, including the timing of the first cleavage, activation of the embryonic genome, compaction and blastocyst formation, can be affected by the culture media and conditions, as well as the production procedure itself. These perturbations can possibly result in a marked decrease in the quality of the resulting blastocysts and may even affect the viability of offspring born after transfer. In vitro procedures such as in vitro production and somatic nuclear transfer of bovine embryos have been shown to be correlated with significant up- or downregulation, de novo induction or silencing of genes critical for undisturbed fetal and neonatal development. These alterations are likely to be caused by epigenetic modifications, such as DNA methylation and histone modifications. Analysis of perturbed epigenetic reprogramming and of the related phenomena, such as genomic imprinting and X-chromosome inactivation, in bovine embryos is promising for understanding the underlying mechanisms of developmental abnormalities, such as large offspring syndrome.

Animals↗
PubMed2002

The SANT domain of Ada2 is required for normal acetylation of histones by the yeast SAGA complex.

Transcription is regulated through chromatin remodeling and histone modification, mediated by large protein complexes. Histone and nucleosome interaction has been shown to be mediated by specific chromatin domains called bromodomains and chromodomains. Here we provide evidence for a similar function of two additional domains within the yeast SAGA complex, containing the histone acetyltransferase Gcn5. We have analyzed deletion and substitution mutations within Gcn5 and Ada2, an interacting protein within SAGA, and have identified substrate recognition functions within the SANT domain of Ada2 and regions of the histone acetyltransferase domain of Gcn5 that are distinct from catalytic function itself. These results suggest that histone and nucleosomal substrate recognition by SAGA involves multiple conserved domains and proteins, beyond those that have been previously identified.

Acetyltransferases↗
PubMed2006

SET-mediated promoter hypoacetylation is a prerequisite for coactivation of the estrogen-responsive pS2 gene by PRMT1.

Induction of transcription requires an ordered recruitment of coregulators and specific combinations of histone modifications at the promoter. Occurrence of histone H4 arginine (Arg) 3 methylation by protein arginine methyltransferase 1 (PRMT1) represents an early promoter event in ER (estrogen receptor)-regulated gene activation. However, its in vivo significance in ER signaling and the prerequisites for PRMT1 recruitment to promoters have not been established yet. We show here that endogenous PRMT1 is a crucial and non-redundant coactivator of ER-mediated pS2 gene induction in MCF7 cells. By investigating promoter requirements for PRMT1 recruitment we find that the patient SE translocation (SET) protein, which was reported to protect histone tails from acetylation, associates with the uninduced pS2 gene promoter and dissociates early upon estrogen treatment. Knockdown of SET or trichostatin A (TSA) treatment causes premature acetylation of H4 and abrogation of H4 Arg3 methylation at the pS2 gene promoter resulting in diminished transcriptional induction. Thus, SET prevents promoter acetylation and is a prerequisite for the initial acetylation-sensitive steps of pS2 gene activation, namely PRMT1 function. Similar to pS2 we identify lactoferrin as a PRMT1-dependent and TSA-sensitive ER target gene. In contrast, we find that the C3 gene, another ER target, is activated in a PRMT1-independent manner and that SET is involved in C3 gene repression. These findings establish the existence of PRMT1-dependent and -independent ER target genes and show that proteins guarding promoter hypoacetylation, like SET, execute a key function in the coactivation process by PRMT1.

Acetylation↗