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PubMed2003

Chromatin dynamics in the male meiotic prophase.

During the male meiotic prophase in mouse and man, pairing and recombination of homologous chromosomes is accompanied by changes in chromatin structure. In this review, the dynamics of assembly and disassembly of the chromatin-associated complexes that mediate sister chromatid cohesion (cohesin) and maintain chromosome pairing (the synaptonemal complex) are described. Special features of the meiotic S phase are discussed, and also the dynamics of several key players that act together after the S phase at sites of meiotic double-strand break DNA repair. Current knowledge on histone modifications that occur during the male meiotic prophase is discussed, with special attention for the inactive chromatin of the X and Y chromosomes that constitutes the sex body. Finally, it is discussed that in the future, it will be possible to view the true chromatin dynamics during male meiosis in time, in living cells, through analysis of fluorescent-tagged proteins expressed in transgenic mice, using advanced fluorescent microscopy techniques.

Animals↗
PubMed2004

Molecular mechanisms of E2F-dependent activation and pRB-mediated repression.

Alterations in transcription of genes regulated by members of the E2F family of transcription factors can be viewed as a measure of the ebb and flow in a constantly evolving battle between repressor and activator complexes. Various chromatin regulatory complexes have been linked to Rb/E2F proteins, and changes in histone modifications correlate with states of E2F-dependent transcription. E2F has traditionally been viewed in the context of cell-cycle control. However, several recent studies have revealed a new aspect of E2F function in which pRB/E2F-family proteins confer stable repression of transcription. Such repression is evident in both actively proliferating cells and in cells that have withdrawn from the cell cycle.

Acetyltransferases↗
PubMed2006

Involvement of AGO1 and AGO2 in mammalian transcriptional silencing.

Duplex RNAs complementary to messenger RNA inhibit translation in mammalian cells by RNA interference (RNAi). Studies have reported that RNAs complementary to promoter DNA also inhibit gene expression. Here we show that the human homologs of Argonaute-1 (AGO1) and Argonaute-2 (AGO2) link the silencing pathways that target mRNA with pathways mediating recognition of DNA. We find that synthetic antigene RNAs (agRNAs) complementary to transcription start sites or more upstream regions of gene promoters inhibit gene transcription. This silencing occurs in the nucleus, requires high promoter activity and does not necessarily require histone modification. AGO1 and AGO2 associate with promoter DNA in cells treated with agRNAs, and inhibiting expression of AGO1 or AGO2 reverses transcriptional and post-transcriptional silencing. Our data indicate key linkages and important mechanistic distinctions between transcriptional and post-transcriptional silencing pathways in mammalian cells.

Argonaute Proteins↗
PubMed2005

The SET domain protein Metnase mediates foreign DNA integration and links integration to nonhomologous end-joining repair.

The molecular mechanism by which foreign DNA integrates into the human genome is poorly understood yet critical to many disease processes, including retroviral infection and carcinogenesis, and to gene therapy. We hypothesized that the mechanism of genomic integration may be similar to transposition in lower organisms. We identified a protein, termed Metnase, that has a SET domain and a transposase/nuclease domain. Metnase methylates histone H3 lysines 4 and 36, which are associated with open chromatin. Metnase increases resistance to ionizing radiation and increases nonhomologous end-joining repair of DNA doublestrand breaks. Most significantly, Metnase promotes integration of exogenous DNA into the genomes of host cells. Therefore, Metnase is a nonhomologous end-joining repair protein that regulates genomic integration of exogenous DNA and establishes a relationship among histone modification, DNA repair, and integration. The data suggest a model wherein Metnase promotes integration of exogenous DNA by opening chromatin and facilitating joining of DNA ends. This study demonstrates that eukaryotic transposase domains can have important cell functions beyond transposition of genetic elements.

Amino Acid Sequence↗
PubMed2007

RhoB is frequently downregulated in non-small-cell lung cancer and resides in the 2p24 homozygous deletion region of a lung cancer cell line.

Identification of a homozygous deletion in cancer cells provides strong evidence for the location of a tumor suppressor gene (TSG). We analyzed the 2p24 homozygous deletion of a non-small-cell lung cancer (NSCLC) cell line, NCI-H2882, and found that the deletion size was 3.7 Mbp. Since RhoB, which has been suggested to be a candidate TSG, was located in this region, we analyzed RhoB for alterations in NSCLC. Although we found no mutations in 48 cell lines including 20 NSCLCs, a loss of heterozygosity (LOH) analysis in 128 primary NSCLCs showed that 25 of 62 informative samples had LOH at the RhoB locus. Northern blot analysis of 28 cell lines (including 15 NSCLCs) indicated that RhoB expression was downregulated in 27. We analyzed RhoB expression in 112 primary NSCLCs with immunohistochemistry and found no or a weak RhoB expression in 33 (42%) of 78 adenocarcinomas, whereas we found it in 29 (94%) of 31 squamous cell carcinomas. No or a weak expression of RhoB was more frequently observed in poorly- or moderately-differentiated adenocarcinomas than in well-differentiated ones (p = 0.0014). Furthermore, no or a weak expression of RhoB indicated a tendency to poor patient prognosis. Although hypermethylation was not found at the promoter region, the RhoB expression in NSCLC cell lines was induced by histone deacetylase inhibition, suggesting that RhoB downregulation may be due to histone modification. The present study demonstrates that RhoB expression is frequently downregulated in NSCLCs by multiple mechanisms, suggesting that RhoB is a candidate TSG for NSCLC.

Aged↗
PubMed2005

How to pack the genome for a safe trip.

The transformation of the somatic chromatin into a unique and highly compact structure occurring during the post-meiotic phase of spermatogenesis is one of the most dramatic known processes of chromatin remodeling. Paradoxically, no information is available on the mechanisms controlling this specific reorganization of the haploid cell genome. The only existing hints suggest a role for histone variants, as well as for stage-specific post-translational histone modifications,before and during the incorporation of testis-specific basic nuclear proteins. Moreover, the exact functions of the latter remain obscure. This chapter summarizes the major chromatin-associated events taking place during the post-meiotic differentiation of male haploid cells in mammals and discusses some of the basic issues that remain to be solved to finally understand chromatin remodeling during spermatogenesis.

Animals↗
PubMed2006

Deficient expression of the DPD gene is caused by epigenetic modification in biliary tract cancer cells, and induces high sensitivity to 5-FU treatment.

5-FU is the drug most frequently used to treat biliary tract cancer, while dihydropyrimidine dehydrogenase (DPD) is known to be a principal factor in 5-FU drug resistance. However, whether DPD activity and mRNA levels correlate with response to 5-FU is unknown for biliary tract cancers. The precise mechanism of DPD regulation also remains to be elucidated. In the present study, we quantitatively analyzed DPD mRNA in 8 biliary tract cancer cell lines using real-time RT-PCR, and assessed whether DPD mRNA levels correlate with DPD activity or the sensitivity to 5-FU. Finally, we examined the epigenetic gene silencing of DPD using one of the 8 lines, a gallbladder cancer cell line with deficient DPD expression, KMG-C. Strong correlation was found between DPD activity and DPD mRNA expression in the 8 cancer cell lines (R=0.797, P=0.0148). DPD mRNA expression and DPD activity exhibited positive correlation with the IC50 for 5-FU (R=0.658, R=0.644, respectively), although these relationships were not statistically significant. In the KMGC cells with deficient DPD mRNA levels, restoration of DPD expression was observed by 5-Aza-2' deoxycytidine (5-aza-C) treatment in a dose-dependent manner, suggesting gene suppression by promoter hypermethylation. Combined bisulfite restriction analysis was performed to analyze the methylation on CpG islands around the 5'-flanking region and intron 1 of the DPD gene, however, no methylated CpG sites were identified in these regions. In addition, the restored DPD expression level was more strongly induced by the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), than 5-aza-C treatment. These findings suggest that other mechanisms, including histone modification, may be important for DPD suppression. In conclusion, these results may aid the selection of 5-FU chemotherapy following determination of DPD expression in biliary tract cancers. Furthermore, epigenetic gene silencing appears to be an important mechanism of DPD suppression in biliary tract cancer.

Antimetabolites, Antineoplastic↗
PubMed2005

Immunoglobulin locus silencing and allelic exclusion.

Lymphocytes are characterised by monoclonal expression of antigen receptors. This is achieved by silencing of one of two homologous antigen receptor alleles, a process known as allelic exclusion. This process is regulated both before and after V(D)J recombination, by a variety of mechanisms. These include nuclear localisation, changes in chromatin structure and histone modifications, non-coding sense and antisense RNA transcription, epigenetic alterations at the DNA level, feedback signalling from expressed alleles, locus contraction and decontraction, recruitment to heterochromatin. This review will focus on recent advances in the immunoglobulin heavy and kappa light chain loci. The current picture is of a complex, temporally ordered sequence of events, in which these loci share many contributory mechanisms, but clear and intriguing differences are emerging.

Alleles↗
PubMed2006

Global and gene-specific analyses show distinct roles for Myod and Myog at a common set of promoters.

We used a combination of genome-wide and promoter-specific DNA binding and expression analyses to assess the functional roles of Myod and Myog in regulating the program of skeletal muscle gene expression. Our findings indicate that Myod and Myog have distinct regulatory roles at a similar set of target genes. At genes expressed throughout the program of myogenic differentiation, Myod can bind and recruit histone acetyltransferases. At early targets, Myod is sufficient for near full expression, whereas, at late expressed genes, Myod initiates regional histone modification but is not sufficient for gene expression. At these late genes, Myog does not bind efficiently without Myod; however, transcriptional activation requires the combined activity of Myod and Myog. Therefore, the role of Myog in mediating terminal differentiation is, in part, to enhance expression of a subset of genes previously initiated by Myod.

Acetylation↗
PubMed1998

Histone H4 acetylation during interleukin-2 stimulation of mouse T cells.

Proliferation and cell cycle progression of eukaryotic cells are closely linked to changes in chromatin structure and gene expression. By reversible histone acetylation the cell is able to modulate chromatin condensation and accessibility of specific regions within the chromatin. Here, we examined histone H4 acetylation patterns during growth induction of the murine interleukin-2 dependent T cell line B6.1. In order to detect acetylation on each of the four potential target residues we produced a set of antibodies recognizing specifically acetylated lysine 5, 8, 12 and 16 in the N-terminal tail of histone H4. Acetylation was generally low in resting T cells, but increased after stimulation with a specific kinetics for each lysine. Lysine 16 was acetylated during the G1 phase and deacetylated during S phase. H4 acetylation on lysine 5, 8 and 12, in contrast, was induced before cells started to replicate, and persisted until cells entered mitosis. Treatment of resting B6.1 cells with the specific deacetylase inhibitor trichostatin A (TSA) led to H4 hyperacetylation at all four lysine residues indicating that the histone modification can occur in the absence of replication. After release from TSA treatment normal H4 acetylation levels were reestablished by extremely rapid deacetylation of lysines 5, 8, 12 and 16. The deacetylation step was 60-100 times faster than TSA induced acetylation and equally efficient in resting and exponentially growing T cells. Our results indicate the presence of cell cycle regulated lysine specific acetylating and deacetylating activities in mouse T cells.

Acetylation↗
PubMed2004

YY1 DNA binding and PcG recruitment requires CtBP.

We found that mammalian Polycomb group (PcG) protein YY1 can bind to Polycomb response elements in Drosophila embryos and can recruit other PcG proteins to DNA. PcG recruitment results in deacetylation and methylation of histone H3. In a CtBP mutant background, recruitment of PcG proteins and concomitant histone modifications do not occur. Surprisingly, YY1 DNA binding in vivo is also ablated. CtBP mutation does not result in YY1 degradation or transport from the nucleus, suggesting a mechanism whereby YY1 DNA binding ability is masked. These results reveal a new role for CtBP in controlling YY1 DNA binding and recruitment of PcG proteins to DNA.

Alcohol Oxidoreductases↗
PubMed2002

Further understanding of the beta-globin locus regulation at the molecular level: looping or linking models?

The human beta-globin locus is a classic model of the eukaryotic multigene family with tissue- and temporally specific expression. Over the past few years, great advances have been achieved in studies of beta-globin locus regulation. The dominant role of the beta-globin locus control region (LCR) in chromatin opening and developmental switching has been challenged, and elements beyond the LCR have been studied in depth. More recently, the fields of research have been expanded to intergenic transcription, nuclear localization and histone modification. Several models have been proposed to elucidate the regulation mechanism; among them, the looping and linking models are the most prevalent. Different models are the summarization of the observations made at different times and a persuasive model must be based on a systematic understanding of the numerous observations. The objective of this review is to provide an overview of progress in the area of beta-globin regulation and then to discuss models for it.

Cell Nucleus↗
PubMed2005

Methyl-CpG-binding proteins in cancer: blaming the DNA methylation messenger.

In recent years, epigenetic alterations have come to prominence in cancer research. In particular, hypermethylation of CpG islands located in the promoter regions of tumor-suppressor genes is now firmly established as an important mechanism for gene inactivation in cancer. One of the most remarkable achievements in the field has been the identification of the methyl-CpG-binding domain family of proteins, which provide mechanistic links between specific patterns of DNA methylation and histone modifications. Although many of the current data indicate that methyl-CpG-binding proteins play a key role in maintaining a transcriptionally inactive state of methylated genes, MBD4 is also known to be involved in excision repair of T:G mismatches. The latter is a member of this family of proteins and appears to play a role in reducing mutations at 5-methylcytosine. This review examines the contribution of methyl-CpG-binding proteins in the epigenetic pathway of cancer.

Animals↗
PubMed2003

Epigenetic dynamics of imprinted X inactivation during early mouse development.

The initiation of X-chromosome inactivation is thought to be tightly correlated with early differentiation events during mouse development. Here, we show that although initially active, the paternal X chromosome undergoes imprinted inactivation from the cleavage stages, well before cellular differentiation. A reversal of the inactive state, with a loss of epigenetic marks such as histone modifications and polycomb proteins, subsequently occurs in cells of the inner cell mass (ICM), which give rise to the embryo-proper in which random X inactivation is known to occur. This reveals the remarkable plasticity of the X-inactivation process during preimplantation development and underlines the importance of the ICM in global reprogramming of epigenetic marks in the early embryo.

Acetylation↗
PubMed2006

Loss of DNA methylation and histone H4 lysine 20 trimethylation in human breast cancer cells is associated with aberrant expression of DNA methyltransferase 1, Suv4-20h2 histone methyltransferase and methyl-binding proteins.

Cancer cells are characterized by epigenetic dysregulation, including global genome hypomethylation, regional hypo- and hypermethylation, altered histone modifications, and disturbed genomic imprinting. Despite the long-established fact that global DNA hypomethylation is a common feature of tumors, very little is known about evolution of this and other epigenetic alterations during tumor progression. The present study was undertaken to characterize the status of epigenetic dysregulation in three human breast cancer cell lines (MCF-7, MDA-MB-231 and MDA-MB-231(S30) that represent different stages of human breast cancer. Our data show that breast cancer cells are characterized by significant alterations in cellular epigenetic status compared to non- tumorigenic MCF-10-2A epithelial breast cells. Interestingly, more malignant MDA-MB- 231 human breast cancer cells have a more prominent loss of DNA methylation accompanied by altered expression of maintenance DNA methyltransferase DNMT1, methyl-binding proteins MeCP2 and MBD2, decreased trimethylation of lysine 20 of histone H4 and hyperacetylation of histone H4 compared to MCF-7 cells. The decrease in trimethylation of lysine 20 of histone H4 in MDA-MB-231 cells was accompanied by diminished expression of Suv4-20h2 histone methyltransferase. The results of present study demonstrate that MDA-MB-231 cells have more extensive epigenenic alterations than MCF-7. These results demonstrate that human breast cancer cells are characterized by prominent epigenetic alterations which are associated with increased malignant properties of cancer cells. Such epigenetic dysregulation may contribute to and may be indicative of the formation of a more aggressive tumor phenotype during tumor progression.

Breast Neoplasms↗
PubMed2005

Hyperacetylated chromatin domains: lessons from heterochromatin.

A small but growing number of loci that exhibit covalent histone modifications, such as hyperacetylation, over broad regions of 10 kb or more have been characterized. These hyperacetylated domains occur exclusively at loci containing highly expressed, tissue-specific genes, and the available evidence suggests that they are involved in the activation of these genes. Although to date little is known concerning the formation or function of these domains, rather more is known concerning repressive, heterochromatic domains, and the example provided by heterochromatin may be instructive in considering mechanisms of active domain formation.

Acetylation↗
PubMed2006

DNA methylation in plants.

DNA in plants is highly methylated, containing 5-methylcytosine (m5C) and N6-methyladenine (m6A); m5C is located mainly in symmetrical CG and CNG sequences but it may occur also in other non-symmetrical contexts. m6A but not m5C was found in plant mitochondrial DNA. DNA methylation in plants is species-, tissue-, organelle- and age-specific. It is controlled by phytohormones and changes on seed germination, flowering and under the influence of various pathogens (viral, bacterial, fungal). DNA methylation controls plant growth and development, with particular involvement in regulation of gene expression and DNA replication. DNA replication is accompanied by the appearance of under-methylated, newly formed DNA strands including Okazaki fragments; asymmetry of strand DNA methylation disappears until the end of the cell cycle. A model for regulation of DNA replication by methylation is suggested. Cytosine DNA methylation in plants is more rich and diverse compared with animals. It is carried out by the families of specific enzymes that belong to at least three classes of DNA methyltransferases. Open reading frames (ORF) for adenine DNA methyltransferases are found in plant and animal genomes, and a first eukaryotic (plant) adenine DNA methyltransferase (wadmtase) is described; the enzyme seems to be involved in regulation of the mitochondria replication. Like in animals, DNA methylation in plants is closely associated with histone modifications and it affects binding of specific proteins to DNA and formation of respective transcription complexes in chromatin. The same gene (DRM2) in Arabidopsis thaliana is methylated both at cytosine and adenine residues; thus, at least two different, and probably interdependent, systems of DNA modification are present in plants. Plants seem to have a restriction-modification (R-M) system. RNA-directed DNA methylation has been observed in plants; it involves de novo methylation of almost all cytosine residues in a region of siRNA-DNA sequence identity; therefore, it is mainly associated with CNG and non-symmetrical methylations (rare in animals) in coding and promoter regions of silenced genes. Cytoplasmic viral RNA can affect methylation of homologous nuclear sequences and it maybe one of the feedback mechanisms between the cytoplasm and the nucleus to control gene expression.

Adenine↗
PubMed2007

Nutrient starvation promotes condensin loading to maintain rDNA stability.

Nutrient starvation or rapamycin treatment, through inhibition of target of rapamycin, causes condensation of ribosomal DNA (rDNA) array and nucleolar contraction in budding yeast. Here we report that under such conditions, condensin is rapidly relocated into the nucleolus and loaded to rDNA tandem repeats, which is required for rDNA condensation. Rpd3-dependent histone deacetylation is necessary and sufficient for condensin's relocalization and loading to rDNA array, suggesting that histone modification plays a regulatory role for condensin targeting. Rapamycin independently, yet coordinately, inhibits rDNA transcription and promotes condensin loading to rDNA array. Unexpectedly, we found that inhibition of rDNA transcription in the absence of condensin loading leads to rDNA instability. Our data suggest that enrichment of condensin prevents rDNA instability during nutrient starvation. Together, these observations unravel a novel role for condensin in the maintenance of regional genomic stability.

Adenosine Triphosphatases↗