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PubMed2006

Constitutive histone H2AX phosphorylation and ATM activation, the reporters of DNA damage by endogenous oxidants.

DNA in live cells undergoes continuous oxidative damage caused by metabolically generated endogenous as well as external oxidants and oxidant-inducers. The cumulative oxidative DNA damage is considered the key factor in aging and senescence while the effectiveness of anti-aging agents is often assessed by their ability to reduce such damage. Oxidative DNA damage also preconditions cells to neoplastic transformation. Sensitive reporters of DNA damage, particularly the induction of DNA double-strand breaks (DSBs), are activation of ATM, through its phosphorylation on Ser 1981, and phosphorylation of histone H2AX on Ser 139; the phosphorylated form of H2AX has been named gammaH2AX. We review the observations that constitutive ATM activation (CAA) and H2AX phosphorylation (CHP) take place in normal cells as well in the cells of tumor lines untreated by exogenous genotoxic agents. We postulate that CAA and CHP, which have been measured by multiparameter cytometry in relation to the cell cycle phase, are triggered by oxidative DNA damage. This review also presents the findings on differences in CAA and CHP in various cell lines as well as on the effects of several agents and growth conditions that modulate the extent of these histone and ATM modifications. Specifically, described are effects of the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC), and the glutathione synthetase inhibitor buthionine sulfoximine (BSO) as well as suppression of cell metabolism by growth at higher cell density or in the presence of the glucose antimetabolite 2-deoxy-D-glucose. Collectively, the reviewed data indicate that multiparameter cytometric measurement of the level of CHP and/or CAA allows one to estimate the extent of ongoing oxidative DNA damage and to measure the DNA protective-effects of antioxidants or agents that reduce or amplify generation of endogenous ROS.

Acetylcysteine↗
PubMed2002

Coupling cAMP signaling to transcription in the liver: pivotal role of CREB and CREM.

Transcriptional factors binding to cAMP-responsive elements (CREs) in the promoters of various genes belong to the basic domain-leucine zipper superfamily and are composed of three genes in mammals, CREB, CREM, and ATF-1. A large number of CREB, CREM, and ATF-1 proteins are generated by posttranscriptional events, mostly alternative splicing, and regulate gene expression by acting as activators or repressors. Activation is classically brought about by signaling-dependent phosphorylation of a key acceptor site (Ser133 in CREB) by a number of possible kinases, including PKA, CamKIV, and Rsk-2. Phosphorylation is the prerequisite for the interaction of CBP (CREB-binding protein), a co-activator that has also histone acetyltransferase activity. Repression may involve dynamic dephosphorylation of the activators and thus decreased association with CBP. Another pathway of transcriptional repression on CRE sites implicates the inducible repressor ICER (inducible cAMP early repressor), a product of the CREM gene. Being an inducible repressor, ICER is involved in autoregulatory feedback loops of transcription that govern the down-regulation of early response genes, such as the proto-oncogene c-fos. The liver represents a remarkable physiological setting where cAMP-responsive signaling plays a major role. Indeed, a finely tuned program of gene expression is triggered by partial hepatectomy, so that through specific checkpoints a coordinated regeneration of the tissue is obtained. Temporal kinetics of transcriptional activation after hepatectomy reveals a pattern of early induction for several genes, some of them controlled by the CREB/CREM transcription factors. An important role of CREM in liver physiology was suggested by the robust induction of ICER after partial hepatectomy. The delay in tissue regeneration in CREM-deficient mice confirmed the important function of this factor in regulating hepatocyte proliferation. As gene induction is accompanied by critical changes in chromatin organization, the deciphering of the specific modification codes that histones display during liver regeneration and physiology will provide exciting new insights into the dynamics of chromatin architecture.

Animals↗
PubMed2003

Silencing of transgene transcription precedes methylation of promoter DNA and histone H3 lysine 9.

Transgenes stably integrated into cells or animals in many cases are silenced rapidly, probably under the influence of surrounding endogenous condensed chromatin. This gene silencing correlates with repressed chromatin structure marked by histone hypoacetylation, loss of methylation at H3 lysine 4, increase of histone H3 lysine 9 methylation as well as CpG DNA methylation at the promoter. However, the order and the timing of these modifications and their impact on transcription inactivation are less well understood. To determine the temporal order of these events, we examined a model system consisting of a transgenic cassette stably integrated in chicken erythroid cells. We found that histone H3 and H4 hypoacetylation and loss of methylation at H3 lysine 4 all occurred during the same window of time as transgene inactivation in both multicopy and low-copy-number lines. These results indicate that these histone modifications were the primary events in gene silencing. We show that the kinetics of silencing exclude histone H3 K9 and promoter DNA methylation as the primary causative events in our transgene system.

Acetylation↗
PubMed2006

Transmission of modified nucleosomes from the mouse male germline to the zygote and subsequent remodeling of paternal chromatin.

Rapidly after gamete fusion, the sperm nucleus loses its specific chromatin conformation and the DNA is repopulated with maternally derived nucleosomes. We evaluated the nature of paternally derived nucleosomes and the dynamics of sperm chromatin remodeling in the zygote directly after gamete fusion. We observed histone H4 acetylated at K8 or K12 already prior to full decondensation of the sperm nucleus, suggesting that these marks are transmitted by the spermatozoon. Tracking down the origin of H4K8ac and H4K12ac during spermiogenesis revealed the retention of nucleosomes with these modifications in the chromocenter of elongating spermatids. We show that sperm constitutive heterochromatin is enriched for nucleosomes carrying specific histone modifications which are transmitted to the zygote. Our results suggest an epigenetic mechanism for inheritance of chromosomal architecture. Furthermore, up to pronucleus formation, histone acetylation and phosphorylation build up in a cascade-like fashion in the paternal chromatin. After formation of the pronucleus, a subset of these marks is removed from the heterochromatin, which suggests a reestablishment of the euchromatin-heterochromatin partition.

Acetylation↗
PubMed2002

Recruitment of O-GlcNAc transferase to promoters by corepressor mSin3A: coupling protein O-GlcNAcylation to transcriptional repression.

Transcription factors and RNA polymerase II can be modified by O-linked N-acetylglucosamine (O-GlcNAc) monosaccharides at serine or threonine residues, yet the precise functional roles of this modification are largely unknown. Here, we show that O-GlcNAc transferase (OGT), the enzyme that catalyzes this posttranslational modification, interacts with a histone deacetylase complex by binding to the corepressor mSin3A. Functionally, OGT and mSin3A cooperatively repress transcription in parallel with histone deacetylation. We propose that mSin3A targets OGT to promoters to inactivate transcription factors and RNA polymerase II by O-GlcNAc modification, which acts in concert with histone deacetylation to promote gene silencing in an efficient and specific manner.

Animal Population Groups↗
PubMed2006

Phosphorylation of histone H4 Ser1 regulates sporulation in yeast and is conserved in fly and mouse spermatogenesis.

Sporulation in Saccharomyces cerevisiae is a highly regulated process wherein a diploid cell gives rise to four haploid gametes. In this study we show that histone H4 Ser1 is phosphorylated (H4 S1ph) during sporulation, starting from mid-sporulation and persisting to germination, and is temporally distinct from earlier meiosis-linked H3 S10ph involved in chromosome condensation. A histone H4 S1A substitution mutant forms aberrant spores and has reduced sporulation efficiency. Deletion of sporulation-specific yeast Sps1, a member of the Ste20 family of kinases, nearly abolishes the sporulation-associated H4 S1ph modification. H4 S1ph may promote chromatin compaction, since deletion of SPS1 increases accessibility to antibody immunoprecipitation; furthermore, either deletion of Sps1 or an H4 S1A substitution results in increased DNA volume in nuclei within spores. We find H4 S1ph present during Drosophila melanogaster and mouse spermatogenesis, and similar to yeast, this modification extends late into sperm differentiation relative to H3 S10ph. Thus, H4 S1ph may be an evolutionarily ancient histone modification to mark the genome for gamete-associated packaging.

Animals↗
PubMed2004

Mechanisms of HP1-mediated gene silencing in Drosophila.

Heterochromatin Protein 1 (HP1) is a structural component of silent chromatin at telomeres and centromeres. Euchromatic genes repositioned near heterochromatin by chromosomal rearrangements are typically silenced in an HP1-dependent manner. Silencing is thought to involve the spreading of heterochromatin proteins over the rearranged genes. HP1 associates with centric heterochromatin through an interaction with methylated lysine 9 of histone H3, a modification generated by SU(VAR)3-9. The current model for spreading of silent chromatin involves HP1-dependent recruitment of SU(VAR)3-9, resulting in the methylation of adjacent nucleosomes and association of HP1 along the chromatin fiber. To address mechanisms of silent chromatin formation and spreading, HP1 was fused to the DNA-binding domain of the E. coli lacI repressor and expressed in Drosophila melanogaster stocks carrying heat shock reporter genes positioned 1.9 and 3.7 kb downstream of lac operator repeats. Association of lacI-HP1 with the repeats resulted in silencing of both reporter genes and correlated with a closed chromatin structure consisting of regularly spaced nucleosomes, similar to that observed in centric heterochromatin. Chromatin immunoprecipitation experiments demonstrated that HP1 spread bi-directionally from the tethering site and associated with the silenced reporter transgenes. To examine mechanisms of spreading, the effects of a mutation in Su(var)3-9 were investigated. Silencing was minimally affected at 1.9 kb, but eliminated at 3.7 kb, suggesting that HP1-mediated silencing can operate in a SU(VAR)3-9-independent and -dependent manner.

Animals↗
PubMed2004

Trypanosomatid histones.

The histones are responsible for packaging and regulating access to eukaryotic genomes. Trypanosomatids are flagellated protists that diverged early from the eukaryotic lineage and include parasites that cause disease in humans and other mammals. Here, we review the properties of histones in parasitic trypanosomatids, from gene organization and sequence to expression, post-translational modification and function within chromatin. Phylogenetic and experimental analysis indicates that certain specifically conserved histone sequence motifs, particularly within the N-terminal 'tail' domains, possibly represent functionally important modification substrates conserved throughout the eukaryotic lineage. For example, histone H3 contains a highly conserved methylation substrate. Trypanosomatids also possess at least three variant histones. Among these is an orthologue of H2A.Z, a histone involved in protecting 'active' chromatin from silencing in yeast. Histones provide docking platforms for a variety of regulatory factors. The presence of histone modification and variant histones in trypanosomatids therefore represents evidence for a network that provides the discrimination required to regulate transcription, recombination, repair and chromosome replication and segregation.

Animals↗
PubMed2006

Epigenetics and cancer: altered chromatin remodeling via Snf5 loss leads to aberrant cell cycle regulation.

The term 'epigenetics' refers to heritable changes in gene function that occur in the absence of any change in DNA sequence. Perturbations of epigenetic gene regulation may play a critical role in the genesis of most, if not all, cancers. These alterations include changes in covalent modifications of DNA and histones as well as non covalent changes in nucleosome positioning. Covalent epigenetic modifications have been the main focus of cancer investigation, perhaps because they are more readily assayed and understood than non covalent modifications. Recently, evidence has emerged demonstrating that perturbation of complexes that remodel the structure of chromatin by mobilizing nucleosomes may have a key role in tumor suppression and oncogenic transformation. For example, Snf5 (Ini1/Baf47/Smarcb1), a core component of the Swi/Snf ATPase chromatin remodeling complex, is a potent tumor suppressor that is specifically inactivated in lethal childhood cancers. Notably, these cancers may serve as a paradigm for epigenetic cancers as, despite their extremely aggressive nature, the majority have an entirely normal karyotype with only microdeletions at the Snf5 locus. Recent investigations have shed light upon the mechanistic basis of Snf5 function by demonstrating that Snf5 and the Swi/Snf complex regulate the cell cycle and cooperate with p53 to prevent oncogenic transformation.

Animals↗
PubMed2007

Epigenetic control of nuclear architecture.

The cell nucleus is a highly structured compartment where nuclear components are thought to localize in non-random positions. Correct positioning of large chromatin domains may have a direct impact on the localization of other nuclear components, and can therefore influence the global functionality of the nuclear compartment. DNA methylation of cytosine residues in CpG dinucleotides is a prominent epigenetic modification of the chromatin fiber. DNA methylation, in conjunction with the biochemical modification pattern of histone tails, is known to lock chromatin in a close and transcriptionally inactive conformation. The relationship between DNA methylation and large-scale organization of nuclear architecture, however, is poorly understood. Here we briefly summarize present concepts of nuclear architecture and current data supporting a link between DNA methylation and the maintenance of large-scale nuclear organization.

Animals↗
PubMed2004

Chromosomal passengers: the four-dimensional regulation of mitotic events.

Chromosomal passengers are proteins that are involved in coordinating the chromosomal and cytoskeletal events of mitosis. The passengers are present in cells as a complex with at least four members: Aurora B, a protein kinase; inner centromeric protein, an activation and targeting subunit; Survivin (function unknown) and Borealin (function also unknown). The kinase is activated at the onset of mitosis, at least partly accomplished by regulation of the levels of its constituents. As mitosis progresses, the kinase complex moves to a highly choreographed series of locations in the mitotic cell, activating key substrates at precise locations and specific times. Functions that require chromosomal passenger activity include chromatin modification (phosphorylation of histone H3), correction of kinetochore attachment errors, aspects of the spindle assembly checkpoint, assembly of a stable bipolar spindle and the completion of cytokinesis. The chromosomal passenger complex provides an essential mechanism for mitotic regulation.

Animals↗
PubMed2004

Ubiquitinated proteins including uH2A on the human and mouse inactive X chromosome: enrichment in gene rich bands.

The inactive X chromosome (Xi) forms a heterochromatic structure in the nucleus that is known to have several modifications to specific histones involving acetylation or methylation. Using three different antibodies in four different cell lines, we demonstrate that the Xi in human and mouse cells is highly enriched in ubiquitinated protein(s), much of which is polyubiquitinated. This ubiquitination appears specific for the Xi as it was not observed for centromeres or other regions of heterochromatin. Results using an antibody specific to ubiquitinated H2A provide a clear link between H2A ubiquitination and gene repression, as visualized across an entire inactive chromosome. Interestingly, the ubiquitination of the chromosome persists into mitosis and can be seen in a reproducible banded pattern. This pattern matches that of Xist RNA which forms bands as it detaches from the mitotic X chromosome. Both ubiquitination and Xist RNA appear enriched in gene dense regions and depleted in gene poor bands, but do not correlate with L1 LINE elements which have been suggested as key to X-inactivation. These results provide evidence that ubiquitination along with Xist RNA plays an important role in the formation of facultative heterochromatin during X-inactivation.

Animals↗
PubMed2005

Molecular mechanisms of epigenetics.

The main epigenetic mechanisms in regulation of gene expression are discussed. The definition of epigenetics and its specific mechanisms including DNA methylation and gene imprinting, modifications of nucleosomal histones associated with silencing or activation of gene transcription, RNA interference, chromosomal silencing, and the role of mobile elements are discussed.

Acetylation↗
PubMed2005

Histone deacetylase inhibitors and cancer: from cell biology to the clinic.

Aberrant gene regulation plays an important role in tumor initiation and progression, and the acetylation of histones is a well understood key component of gene regulation. Histone acetylation involves the opposing activities of the histone acetyltransferases (HATs) and histone deacetylases (HDACs)--histone acetylation is associated with increased transcriptional activity while histone deacetylation is associated with repression of gene expression. In addition, the modification of non-histone proteins by HATs and HDACs is also an important process in regulating gene expression. Several lines of evidence suggest that inappropriate transcriptional activation and repression mediated by HATs and HDACs is a common occurrence in the formation of many different types of cancer. These enzymes thus represent novel molecular targets for which inhibitors are sought that could reprogram transcription and inhibit tumor cell growth and progression. Much of the research has focused on HDAC inhibitors, where several agents have demonstrated in vitro and in vivo activity against different tumor cell models and have entered Phase I clinical trials. HDAC inhibitors are believed to exert their antiproliferative effects by inducing a small set of genes involved in regulating cellular activities such as proliferation and differentiation. Future research is expected to lead to a better understanding of the molecular targets of HDACs and facilitate the development of more potent inhibitors of these enzymes. First results from clinical trials will help to determine the optimal strategy for utilizing these agents for the treatment of cancer patients.

Acetylation↗
PubMed2006

Dynamics, stability and inheritance of somatic DNA methylation imprints.

Recent research highlights the role of CpG methylation in genomic imprinting, histone and chromatin modification, transcriptional regulation, and 'gene silencing' in cancer development. An unresolved issue, however, is the role of stable inheritance of factors that manage epigenetic imprints in renewing or expanding cell populations in soma. Here we propose a mathematical model of CpG methylation that is consistent with the cooperative roles of de novo and maintenance methylation. This model describes (1) the evolution of methylation imprints toward stable, yet noisy equilibria, (2) bifurcations in methylation levels, thus the dual stability of both hypo- and hypermethylated genomic regions, and (3) sporadic transitions from hypo- to hypermethylated equilibria as a result of methylation noise in a finite system of CpG sites. Our model not only affords an explanation of the persistent coexistence of these two equilibria, but also of sporadic changes of site-specific methylation levels that may alter preset epigenetic imprints in a renewing cell population.

Animals↗
PubMed2006

Transcription of gonadotropin beta subunit genes involves cross-talk between the transcription factors and co-regulators that mediate actions of the regulatory hormones.

The gonadotropins LH and FSH have distinct temporal patterns of expression as a result of differential regulation by hormones such as GnRH, steroids and activin. This specific regulation is due to diverse sets of transcription factors that are recruited to the promoters of these genes, and recruit specific co-activator complexes which function to stabilize interactions with the general transcription factors and RNA polymerase II, and also to induce covalent modifications of the histone tails at these gene loci. As these molecular mechanisms are elucidated, the nature of nuclear cross-talk between the various hormonally induced pathways is becoming evident, revealing both negative and positive effects of interacting transcription factors and co-regulators. This paper will review current knowledge on the transcriptional regulation of gonadotropin beta subunit gene expression in the chromatin setting, and will present new data pertaining to nuclear cross-talk between the various endocrine-induced pathways regulating gonadotropin gene transcription.

Animals↗
PubMed2005

Differential localization of MAPK-activated protein kinases RSK1 and MSK1 in mouse brain.

RSK1 and MSK1 are closely related members of the MAP kinase-activated kinase family and are direct substrates and effectors of the well-studied mitogen-activated protein kinases. Although extensively characterized at the biochemical level, little is known about the localization of these protein kinases in the brain. We utilized immunohistochemistry to determine the cellular and subcellular localization of RSK1 and MSK1 in the adult mouse brain. RSK1 is expressed at highest levels in cerebellum, especially in granule neurons and within neuropil of the molecular layer. RSK1 is also expressed in microglia throughout the brain. In a focal trauma model, RSK1 immunoreactivity is increased in activated microglia. RSK1 expression is also prominent in many large pyramidal neurons throughout the brain. At the subcellular level, RSK1 is highly concentrated in the golgi apparatus of both neurons and astroglia. In contrast, MSK1 is expressed at highest levels in striatal and olfactory tubercle neurons and to a lesser degree in cerebellar Purkinje cells. MSK1 is also expressed in a subset of astroglia. At the subcellular level, MSK1 is confined to the nucleus of all expressing cell types. The differential cellular and subcellular localizations of RSK1 and MSK1 suggest divergent functional roles in the brain, with RSK1 poised to regulate membrane trafficking or membrane-localized signaling, and MSK1 involved in modification of nuclear histones and transcription factors.

Animals↗
PubMed2003

Epigenetic theories of cancer initiation.

I argue that carcinogenic insults injure many cells rather than mutate a few. This results from evidence that such insults convert too many cells to a precancerous state and that too many of the converted cells then revert to plausibly involve mutation and its repair; from evidence that the delays between such insults and chemically demonstrable mutations are long enough to easily allow nonmutational mechanisms to work; from evidence that even ionizing radiation first acts on the cytoplasm and mainly affects cells unhit by it; from the fact that such insults induce proto-oncogene expression far too quickly to do so by mutation; and from the fact that fusions of various cells and cell parts show that the tumorous or nontumorous nature of the product depends on its cytoplasmic rather than its nuclear component. I further argue that reduced DNA methylation, modifications of the histone code, and tissue disorganization are the three main mechanisms of epigenetic cancer initiation. Hypomethylation would result from DNA excision repair. Moreover, a methyl-deficient diet is carcinogenic and demethylation is also known to be carcinogenic via the histone code. Finally, I strongly argue for tissue disorganization as a mechanism of cancer initiation. This results from evidence that skin carcinogens disrupt the dermal/epidermal connection and from the fact that tumorigens swiftly disrupt gap junctions, as well as from evidence that such disruption is tumorigenic.

Animals↗