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PubMed2004

Expression of mitochondrial HMGCoA synthase and glutaminase in the colonic mucosa is modulated by bacterial species.

The expression of the colonic mitochondrial 3-hydroxy 3-methyl glutaryl CoA (mHMGCoA) synthase, a key control site of ketogenesis from butyrate, is lower in germ-free (GF) than in conventional (CV) rats. In contrast, the activity of glutaminase is higher. The objective of this study was to investigate whether the intestinal flora can affect gene expression through short chain fatty acid (SCFA) and butyrate production. GF rats were inoculated with a conventional flora (Ino-CV) or with a bacterial strain producing butyrate (Clostridium paraputrificum, Ino-Cp) or not (Bifidobacterium breve, Ino-Bb). In the Ino-CV rats, mHMGCoA synthase expression was restored to the CV values 2 days after the inoculation, i.e. concomitantly with SCFA production. In the Ino-Cp group, but not in the Ino-Bb group, mHMGCoA synthase and glutaminase were expressed at the level observed in the CV rats. These data suggest that the intestinal flora, through butyrate production, could control the expression of colonic mHMGCoA synthase and glutaminase. These modifications in gene expression by butyrate in vivo seem unrelated to a modification of histone acetylation.

Acetylation↗
PubMed1986

Control of gene expression by steroid hormones.

The mechanism of action of steroid hormones involves their interaction with tissue-specific binding sites, and results in a precise modulation of gene expression. Both high-affinity receptors and secondary binding sites exist for steroid hormones in target tissues. Only steroid-receptor complexes were, in several cases, clearly shown to directly regulate transcription by interacting with DNA region(s) close to steroid-controlled genes. However other indications suggest that steroid hormones could also modulate transcription by altering chromatin conformation. These modifications encompass post-traductional modifications of histones and non-histone proteins, as well as changes in the pattern of histone variants. Beside transcription, there are also evidences that steroid hormones can modulate gene expression by regulating some RNA processing events. Whether high-affinity receptors or secondary binding sites directly regulate these events is not known. These observations however suggest that several levels of control might exist for steroid hormones to precisely regulate gene expression.

Animals↗
PubMed2001

Regulation of global acetylation in mitosis through loss of histone acetyltransferases and deacetylases from chromatin.

Histone acetylation, a reversible modification of the core histones, is widely accepted to be involved in remodeling chromatin organization for genetic reprogramming. Histone acetylation is a dynamic process that is regulated by two classes of enzymes, the histone acetyltransferases (HATs) and histone deacetylases (HDACs). Although promoter-specific acetylation and deacetylation has received most of the recent attention, it is superimposed upon a broader acting and dynamic acetylation that profoundly affects many nuclear processes. In this study, we monitored this broader histone acetylation as cells enter and exit mitosis. In contrast to the hypothesis that HATs and HDACs remain bound to mitotic chromosomes to provide an epigenetic imprint for postmitotic reactivation of the genome, we observed that HATs and HDACs are spatially reorganized and displaced from condensing chromosomes as cells progress through mitosis. During mitosis, HATs and HDACs are unable to acetylate or deacetylate chromatin in situ despite remaining fully catalytically active when isolated from mitotic cells and assayed in vitro. Our results demonstrate that HATs and HDACs do not stably bind to the genome to function as an epigenetic mechanism of selective postmitotic gene activation. Our results, however, do support a role for spatial organization of these enzymes within the cell nucleus and their relationship to euchromatin and heterochromatin postmitotically in the reactivation of the genome.

Acetylation↗
PubMed2003

H2AX is required for recombination between immunoglobulin switch regions but not for intra-switch region recombination or somatic hypermutation.

Changes in chromatin structure induced by posttranslational modifications of histones are important regulators of genomic function. Phosphorylation of histone H2AX promotes DNA repair and helps maintain genomic stability. Although B cells lacking H2AX show impaired class switch recombination (CSR), the precise role of H2AX in CSR and somatic hypermutation (SHM) has not been defined. We show that H2AX is not required for SHM, suggesting that the processing of DNA lesions leading to SHM is fundamentally different from CSR. Impaired CSR in H2AX-/- B cells is not due to alterations in switch region transcription, accessibility, or aberrant joining. In the absence of H2AX, short-range intra-switch region recombination proceeds normally while long-range inter-switch region recombination is impaired. Our results suggest a role for H2AX in regulating the higher order chromatin remodeling that facilitates switch region synapsis.

Animals↗
PubMed2001

Physical and functional association of SU(VAR)3-9 and HDAC1 in Drosophila.

Modification of histones can have a dramatic impact on chromatin structure and function. Acetylation of lysines within the N-terminal tail of the histone octamer marks transcriptionally active regions of the genome whereas deacetylation seems to play a role in transcriptional silencing. Recently, the methylation of the histone tails has also been shown to be important for transcriptional regulation and chromosome structure. Here we show by immunoaffinity purification that two activities important for chromatin-mediated gene silencing, the histone methyltransferase SU(VAR)3-9 and the histone deacetylase HDAC1, associate in vivo. The two activities cooperate to methylate pre-acetylated histones. Both enzymes are modifiers of position effect variegation and interact genetically in flies. We suggest a model in which the concerted histone deacetylation and methylation by a SU(VAR)3-9/HDAC1-containing complex leads to a permanent silencing of transcription in particular areas of the genome.

Animals↗
PubMed2006

Epigenetic regulation of chromatin structure and gene function by biotin.

Covalent modifications of histones are a crucial component of epigenetic events that regulate chromatin structures and gene function. Evidence exists that distinct lysine residues in histones are modified by covalent attachment of the vitamin biotin, catalyzed by biotinidase and holocarboxylase synthetase. Biotinylation of histones appears to be conserved across species. The following biotinylation sites were identified using both MS and enzymatic biotinylation of synthetic peptides: K9, K13, K125, K127, and K129 in histone H2A; K4, K9, and K18 in histone H3; and K8 and K12 in histone H4. Evidence was provided that biotinylated histone H4 is enriched in pericentromeric heterochromatin, and that biotinylation of histone H4 participates in gene silencing, mitotic condensation of chromatin, and the cellular response to DNA damage. Biotinylation of histones is a reversible process and depends on the exogenous biotin supply, but the identities of histone debiotinylases remain uncertain. We propose that some effects of biotin deficiency can be attributed to abnormal chromatin structures.

Biotin↗
PubMed1999

Chromatin remodeling and transcriptional regulation.

Extensive studies in the past few years have begun to demonstrate that chromosome structure plays a critical role in transcriptional regulation. Two highly conserved mechanisms for altering chromosome structure have been identified: 1) post-translational modification of histones and 2) adenosine triphosphate (ATP)-dependent chromosome remodeling. Acetylation of histone lysine residues has been known for three decades to be associated with transcriptional activation. Recent discoveries, however, show that a number of transcriptional regulators are histone acetylases or histone deacetylases. Specific DNA-binding transcription factors recruit histone acetylases and deacetylases to promoters to activate or repress transcription. These results strongly support the notion that histone acetylation and deacetylation play an important role in transcriptional regulation. Recent findings have also provided insight into the molecular mechanisms by which ATP-dependent chromosome-remodeling activities participate in transcriptional regulation. Furthermore, some ATP-dependent chromosome-remodeling activities have been shown to complex with histone deacetylases. In the complexes studied to date, the ATP-dependent chromosome-remodeling activity enhances the histone deacetylase activity. Therefore, the two mechanisms appear to work in concert to achieve precise control of transcription. Disruption of chromosome remodeling has been linked to a number of diseases, and a complete understanding of the complex chromosome-remodeling machinery may lead to the development of new therapies.

Acetylation↗
PubMed2000

Co-repressors 2000.

In the last 5 years, many co-repressors have been identified in eukaryotes that function in a wide range of species, from yeast to Drosophila and humans. Co-repressors are coregulators that are recruited by DNA-bound transcriptional silencers and play essential roles in many pathways including differentiation, proliferation, programmed cell death, and cell cycle. Accordingly, it has been shown that aberrant interactions of co-repressors with transcriptional silencers provide the molecular basis of a variety of human diseases. Co-repressors mediate transcriptional silencing by mechanisms that include direct inhibition of the basal transcription machinery and recruitment of chromatin-modifying enzymes. Chromatin modification includes histone deacetylation, which is thought to lead to a compact chromatin structure to which the accessibility of transcriptional activators is impaired. In a general mechanistic view, the overall picture suggests that transcriptional silencers and co-repressors act in analogy to transcriptional activators and coactivators, but with the opposite effect leading to gene silencing. We provide a comprehensive overview of the currently known higher eukaryotic co-repressors, their mechanism of action, and their involvement in biological and pathophysiological pathways. We also show the different pathways that lead to the regulation of co-repressor-silencer complex formation.

Chromatin↗
PubMed2005

Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping.

The identity and developmental potential of a human cell is specified by its epigenome that is largely defined by patterns of chromatin modifications including histone acetylation. Here we report high-resolution genome-wide mapping of diacetylation of histone H3 at Lys 9 and Lys 14 in resting and activated human T cells by genome-wide mapping technique (GMAT). Our data show that high levels of the H3 acetylation are detected in gene-rich regions. The chromatin accessibility and gene expression of a genetic domain is correlated with hyperacetylation of promoters and other regulatory elements but not with generally elevated acetylation of the entire domain. Islands of acetylation are identified in the intergenic and transcribed regions. The locations of the 46,813 acetylation islands identified in this study are significantly correlated with conserved noncoding sequences (CNSs) and many of them are colocalized with known regulatory elements in T cells. TCR signaling induces 4045 new acetylation loci that may mediate the global chromatin remodeling and gene activation. We propose that the acetylation islands are epigenetic marks that allow prediction of functional regulatory elements.

Acetylation↗
PubMed2002

Establishment and maintenance of a heterochromatin domain.

The higher-order assembly of chromatin imposes structural organization on the genetic information of eukaryotes and is thought to be largely determined by posttranslational modification of histone tails. Here, we study a 20-kilobase silent domain at the mating-type region of fission yeast as a model for heterochromatin formation. We find that, although histone H3 methylated at lysine 9 (H3 Lys9) directly recruits heterochromatin protein Swi6/HP1, the critical determinant for H3 Lys9 methylation to spread in cis and to be inherited through mitosis and meiosis is Swi6 itself. We demonstrate that a centromere-homologous repeat (cenH) present at the silent mating-type region is sufficient for heterochromatin formation at an ectopic site, and that its repressive capacity is mediated by components of the RNA interference (RNAi) machinery. Moreover, cenH and the RNAi machinery cooperate to nucleate heterochromatin assembly at the endogenous mat locus but are dispensable for its subsequent inheritance. This work defines sequential requirements for the initiation and propagation of regional heterochromatic domains.

Alleles↗
PubMed2006

The nucleosome: a little variation goes a long way.

Changes in the overall structure of chromatin are essential for the proper regulation of cellular processes, including gene activation and silencing, DNA repair, chromosome segregation during mitosis and meiosis, X chromosome inactivation in female mammals, and chromatin compaction during apoptosis. Such alterations of the chromatin template occur through at least 3 interrelated mechanisms: post-translational modifications of histones, ATP-dependent chromatin remodeling, and the incorporation (or replacement) of specialized histone variants into chromatin. Of these mechanisms, the exchange of variants into and out of chromatin is the least well understood. However, the exchange of conventional histones for variant histones has distinct and profound consequences within the cell. This review focuses on the growing number of mammalian histone variants, their particular biological functions and unique features, and how they may affect the structure of the nucleosome. We propose that a given nucleosome might not consist of heterotypic variants, but rather, that only specific histone variants come together to form a homotypic nucleosome, a hypothesis that we refer to as the nucleosome code. Such nucleosomes might in turn participate in marking specific chromatin domains that may contribute to epigenetic inheritance.

Animals↗
PubMed2005

Remembering winter: toward a molecular understanding of vernalization.

Exposure to the prolonged cold of winter is an important environmental cue that favors flowering in the spring in many types of plants. The process by which exposure to cold promotes flowering is known as vernalization. In Arabidopsis and certain cereals, the block to flowering in plants that have not been vernalized is due to the expression of flowering repressors. The promotion of flowering is due to the cold-mediated suppression of these repressors. Recent work has demonstrated that covalent modifications of histones in the chromatin of target loci are part of the molecular mechanism by which certain repressors are silenced during vernalization.

Adaptation, Physiological↗
PubMed2006

Identification of a gene network contributing to hypertrophy in callipyge skeletal muscle.

The callipyge mutation in sheep results in postnatal skeletal muscle hypertrophy in the pelvic limbs and loins with little or no effect on anterior skeletal muscles. Associated with the phenotype are changes in the expression of a number of imprinted genes flanking the site of the mutation, which lies in an intergenic region at the telomeric end of ovine chromosome 18. The manner in which these local changes in gene expression are translated into muscle hypertrophy is not known. Microarray-based transcriptional profiling was used to identify differentially expressed genes in longissimus dorsi skeletal muscle samples taken at birth and 12 wk of age from callipyge and wild-type sheep. The phenotype was only expressed at the latter developmental time and associated with decreased type 1 fibers (slow oxidative) and a shift toward type IIx and IIb fibers (fast-twitch glycolytic). We have identified 131 genes in the samples taken at 12 wk of age that were differentially expressed as a function of genotype but not due to the fiber type changes. The gene expression changes occurring as a function of genotype in the samples taken at birth indicated that the transcriptional framework underpinning the phenotype was emerging prior to expression of the phenotype. Eight genes were differentially expressed as a function of genotype at both developmental times. A model is proposed describing a core network of genes and histone epigenetic modifications that is likely to underpin the fiber type changes and muscle hypertrophy characteristic of callipyge sheep.

Animals↗
PubMed2006

Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members.

The breast cancer-associated gene-1 (BRCA1) plays many important functions in multiple biological processes/pathways. Mice homozygous for a targeted deletion of full-length BRCA1 (Brca1Delta11/Delta11) display both increased tumorigenesis and premature aging, yet molecular mechanisms underlying these defects remain elusive. Here, we show that Brca1 deficiency leads to increased expression of several insulin-like growth factor (IGF) signaling axis members in multiple experimental systems, including BRCA1-deficient mice, primary mammary tumors, and cultured human cells. Furthermore, we provide evidence that activation of IGF signaling by BRCA1 deficiency can also occur in a p53-independent fashion. Our data indicate that BRCA1 interacts with the IRS-1 promoter and inhibits its activity that is associated with epigenetic modification of histone H3 and histone H4 to a transcriptional repression chromatin configuration. We further show that BRCA1-deficient mammary tumor cells exhibit high levels of IRS-1, and acute suppression of Irs-1 using RNA interference significantly inhibits growth of these cells. Those observations provide a molecular insight in understanding both fundamental and therapeutic BRCA1-associated tumorigenesis and aging.

Animals↗
PubMed2004

HDAC6 expression is correlated with better survival in breast cancer.

PURPOSE: The structure and function of chromatin can be altered by modifications to histone. Histone acetylation in vivo is a dynamic reversible process governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC6 is a unique isoform among the HDACs, and a gene expression pattern study, with cDNA microarray in MCF-7 cells, showed the HDAC6 gene to be late responsive, estrogen induced, and up-regulated. This led us to hypothesize that there was a link between levels of HDAC6 expression and the metastatic potential of breast cancer and also, therefore, the prognosis of these patients. EXPERIMENTAL DESIGN: In the present study, the level of HDAC6 mRNA expression was analyzed with quantitative real-time reverse transcription-PCR, in 135 female patients with invasive breast cancer. HDAC6 protein expression was also determined by immunohistochemistry. An association was sought between HDAC6 expression and various clinicopathologic factors. RESULTS: HDAC6 mRNA was expressed at significantly higher levels in breast cancer patients with small tumors measuring less than 2 cm, with low histologic grade, and in estrogen receptor alpha- and progesterone receptor-positive tumors. By contrast, no relationship was found between HDAC6 mRNA expression and any of the other clinicopathologic factors, namely, age, menopausal status, and axillary lymph node involvement. Patients expressing high levels of HDAC6 mRNA and protein had a better prognosis than those expressing low levels, in terms of disease-free survival. However, multivariate analysis failed to show that HDAC6 mRNA and protein are an independent prognostic factors for disease-free survival and overall survival. Furthermore, the patients with high levels of HDAC6 mRNA tended to be more responsive to endocrine treatment than those with low levels. Specific HDAC6 staining was found in the nucleus of some normal epithelial cells and in the cytoplasm of the majority of cancer cells. Although postmenopausal patients showed higher HDAC6 protein expression, there were no relationship between protein expression and any other clinicopathologic factors. CONCLUSIONS: We conclude that the levels of HDAC6 mRNA expression may have potential both as a marker of endocrine responsiveness and also as a prognostic indicator in breast cancer. Additional investigations are warranted concerning the relationship between HDAC6 expression and response to endocrine therapy.

Adult↗
PubMed2004

DNA methylation in mouse gametogenesis.

DNA methylation is involved in many biological processes and is particularly important for both development and germ cell differentiation. Several waves of demethylation and de novo methylation occur during both male and female germ line development. This has been found at both the gene and all genome levels, but there is no demonstrated correlation between them. During the postnatal germ line development of spermatogenesis, we found very complex and drastic DNA methylation changes that we could correlate with chromatin structure changes. Thus, detailed studies focused on localization and expression pattern of the chromatin proteins involved in both DNA methylation, histone tails modification, condensin and cohesin complex formation, should help to gain insights into the mechanisms at the origin of the deep changes occurring during this particular period.

Animals↗
PubMed2005

Characterization of sub-nuclear changes in Caenorhabditis elegans embryos exposed to brief, intermediate and long-term anoxia to analyze anoxia-induced cell cycle arrest.

BACKGROUND: The soil nematode C. elegans survives oxygen-deprived conditions (anoxia; <.001 kPa O2) by entering into a state of suspended animation in which cell cycle progression reversibly arrests. The majority of blastomeres of embryos exposed to anoxia arrest at interphase, prophase and metaphase. The spindle checkpoint proteins SAN-1 and MDF-2 are required for embryos to survive 24 hours of anoxia. To further investigate the mechanism of cell-cycle arrest we examined and compared sub-nuclear changes such as chromatin localization pattern, post-translational modification of histone H3, spindle microtubules, and localization of the spindle checkpoint protein SAN-1 with respect to various anoxia exposure time points. To ensure analysis of embryos exposed to anoxia and not post-anoxic recovery we fixed all embryos in an anoxia glove box chamber. RESULTS: Embryos exposed to brief periods to anoxia (30 minutes) contain prophase blastomeres with chromosomes in close proximity to the nuclear membrane, condensation of interphase chromatin and metaphase blastomeres with reduced spindle microtubules density. Embryos exposed to longer periods of anoxia (1-3 days) display several characteristics including interphase chromatin that is further condensed and in close proximity to the nuclear membrane, reduction in spindle structure perimeter and reduced localization of SAN-1 at the kinetochore. Additionally, we show that the spindle checkpoint protein SAN-1 is required for brief periods of anoxia-induced cell cycle arrest, thus demonstrating that this gene product is vital for early anoxia responses. In this report we suggest that the events that occur as an immediate response to brief periods of anoxia directs cell cycle arrest. CONCLUSION: From our results we conclude that the sub-nuclear characteristics of embryos exposed to anoxia depends upon exposure time as assayed using brief (30 minutes), intermediate (6 or 12 hours) or long-term (24 or 72 hours) exposures. Analyzing these changes will lead to an understanding of the mechanisms required for initiation and maintenance of cell cycle arrest in respect to anoxia exposure time as well as order the events that occur to bring about anoxia-induced cell cycle arrest.

Animals↗
PubMed2005

The loss of NKX3.1 expression in testicular--and prostate--cancers is not caused by promoter hypermethylation.

BACKGROUND: Recent studies have demonstrated that the NKX3.1 protein is commonly down-regulated in testicular germ cell tumors (TGCTs) and prostate carcinomas. The homeobox gene NKX3.1 maps to chromosome band 8p21, which is a region frequently lost in prostate cancer, but not in TGCT. Mutations have not been reported in the NKX3.1 sequence, and the gene is hypothesized to be epigenetically inactivated. In the present study we examined the methylation status of the NKX3.1 promoter in relevant primary tumors and cell lines: primary TGCTs (n = 55), intratubular germ cell neoplasias (n = 7), germ cell tumor cell lines (n = 3), primary prostate adenocarcinomas (n = 20), and prostate cancer cell lines (n = 3) by methylation-specific PCR and bisulphite sequencing. RESULTS AND CONCLUSIONS: Down-regulation of NKX3.1 expression was generally not caused by promoter hypermethylation, which was only found in one TGCT. However, other epigenetic mechanisms, such as modulation of chromatin structure or modifications of histones, may explain the lack of NKX3.1 expression, which is seen in most TGCTs and prostate cancer specimens.

Adenocarcinoma↗