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Siavash K Kurdistani

Publications and source records attributed to Siavash K Kurdistani.

10 recordsLinked to original sources
PubMed2005

Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex.

The yeast histone deacetylase Rpd3 can be recruited to promoters to repress transcription initiation. Biochemical, genetic, and gene-expression analyses show that Rpd3 exists in two distinct complexes. The smaller complex, Rpd3C(S), shares Sin3 and Ume1 with Rpd3C(L) but contains the unique subunits Rco1 and Eaf3. Rpd3C(S) mutants exhibit phenotypes remarkably similar to those of Set2, a histone methyltransferase associated with elongating RNA polymerase II. Chromatin immunoprecipitation and biochemical experiments indicate that the chromodomain of Eaf3 recruits Rpd3C(S) to nucleosomes methylated by Set2 on histone H3 lysine 36, leading to deacetylation of transcribed regions. This pathway apparently acts to negatively regulate transcription because deleting the genes for Set2 or Rpd3C(S) bypasses the requirement for the positive elongation factor Bur1/Bur2.

Acetylation↗
PubMed2005

Global histone modification patterns predict risk of prostate cancer recurrence.

Aberrations in post-translational modifications of histones have been shown to occur in cancer cells but only at individual promoters; they have not been related to clinical outcome. Other than being targeted to promoters, modifications of histones, such as acetylation and methylation of lysine and arginine residues, also occur over large regions of chromatin including coding regions and non-promoter sequences, which are referred to as global histone modifications. Here we show that changes in global levels of individual histone modifications are also associated with cancer and that these changes are predictive of clinical outcome. Through immunohistochemical staining of primary prostatectomy tissue samples, we determined the percentage of cells that stained for the histone acetylation and dimethylation of five residues in histones H3 and H4. Grouping of samples with similar patterns of modifications identified two disease subtypes with distinct risks of tumour recurrence in patients with low-grade prostate cancer. These histone modification patterns were predictors of outcome independently of tumour stage, preoperative prostate-specific antigen levels, and capsule invasion. Thus, widespread changes in specific histone modifications indicate previously undescribed molecular heterogeneity in prostate cancer and might underlie the broad range of clinical behaviour in cancer patients.

Acetylation↗
PubMed2004

Function of Drg1/Rit42 in p53-dependent mitotic spindle checkpoint.

Mutations in the Drg1/RTP/Rit42 gene are commonly identified in hereditary neuropathies of the motor and sensory systems. This gene was also identified as a p53 target gene and a differentiation-related, putative metastatic suppressor gene in human colon and prostate cancer. In this study, we show that the Rit42 protein is a microtubule-associated protein that localizes to the centrosomes and participates in the spindle checkpoint in a p53-dependent manner. When ectopically expressed and exposed to spindle inhibitors, Rit42 inhibited polyploidy in several p53-deficient tumor cell lines and increased the population of cells in mitotic arrest. Blocking endogenous Rit42 expression by small interfering RNA in normal human mammary epithelial cells resulted in the disappearance of astral microtubules, and dividing spindle fiber formation was rarely detected. Moreover, these cells underwent microtubule inhibitor-induced reduplication, leading to a polyploidy state. Our findings imply that Rit42 plays a role in the regulation of microtubule dynamics and the maintenance of euploidy.

Adenoviridae↗
PubMed2004

Mapping global histone acetylation patterns to gene expression.

Histone acetyltransferases and deacetylases with specificities for different sites of acetylation affect common chromatin regions. This could generate unique patterns of acetylation that may specify downstream biological processes. To search for existence of these patterns and their relationship to gene activity, we analyzed the genome-wide acetylation profiles for eleven lysines in the four core histones of Saccharomyces cerevisiae. We find that both hyper- and hypoacetylation of individual lysines are associated with transcription, generating distinct patterns of acetylation that define groups of biologically related genes. The genes within these groups are significantly coexpressed, mediate similar physiological processes, share unique cis-regulatory DNA motifs, and are enriched for binding of specific transcription factors. Our data also indicate that the in vivo binding of the transcription factor Bdf1 is associated with acetylation on most lysines but relative deacetylation on H4 lysine 16. Thus, certain acetylation patterns may be used as surfaces for specific protein-histone interactions, providing one mechanism for coordinate regulation of chromatin processes that are biologically related.

Acetylation↗
PubMed2003

In vivo protein-protein and protein-DNA crosslinking for genomewide binding microarray.

Chromatin immunoprecipitation (ChrIP or ChIP) has commonly been used to map protein-DNA interaction sites at specific genomic loci through use of formaldehyde-induced crosslinking. However, formaldehyde alone has proved inadequate for crosslinking of certain proteins such as the yeast histone deacetylase Rpd3. We report here a modified crosslinking procedure that includes a protein-protein crosslinking agent in addition to formaldehyde. Using this double crosslinking method, we have successfully mapped Rpd3 binding sites in vivo. We also describe the use of ChrIP in combination with DNA microarrays (ChrIP-array) to determine the pattern of Rpd3 binding genomewide. This approach couples the versatility of ChrIP with that of microarrays to identify binding patterns that would otherwise be hidden in a gene-by-gene survey.

Base Sequence↗
PubMed2003

Histone acetylation and deacetylation in yeast.

Histone acetylation and deacetylation in the yeast Saccharomyces cerevisiae occur by targeting acetyltransferase and deacetylase enzymes to gene promoters and, in an untargeted and global manner, by affecting most nucleosomes. Recently, new roles for histone acetylation have been uncovered, not only in transcription but also in DNA replication, repair and heterochromatin formation. Interestingly, specific acetylatable lysines can function as binding sites for regulatory factors. Moreover, histone deacetylation is not only repressive but can be required for gene activity.

Acetyltransferases↗
PubMed2002

Requirement of Hos2 histone deacetylase for gene activity in yeast.

Histone deacetylases, typified by class I Rpd3 in the yeast Saccharomyces cerevisiae, have historically been associated with gene repression. We now demonstrate that Hos2, another member of the class I family, binds to the coding regions of genes primarily during gene activation, when it specifically deacetylates the lysines in H3 and H4 histone tails. Moreover, Hos2 is preferentially associated with genes of high activity genome-wide. We also show that Hos2 and an associated factor, Set3, are necessary for efficient transcription. Therefore, our data indicate that, in contrast to other class I histone deacetylases, Hos2 is directly required for gene activation.

Acetylation↗
PubMed2002

Genome-wide binding map of the histone deacetylase Rpd3 in yeast.

We describe the genome-wide distribution of the histone deacetylase and repressor Rpd3 and its associated proteins Ume1 and Ume6 in Saccharomyces cerevisiae. Using a new cross-linking protocol, we found that Rpd3 binds upstream of many individual genes and upstream of members of gene classes with similar functions in anabolic processes. In addition, Rpd3 is preferentially associated with promoters that direct high transcriptional activity. We also found that Rpd3 was absent from large sub-telomeric domains. We show by co-immunoprecipitation and by the high similarity of their binding maps that Ume1 interacts with Rpd3. In contrast, despite the known role of Ume6 in Rpd3 recruitment, only a limited number of the genes targeted by Rpd3 are also enriched for (or targeted by) Ume6. This suggests that Rpd3 is brought to many promoters by alternative recruiters, some of which may bind the putative cis-regulatory DNA elements that we have identified in sets of Rpd3 target genes. Finally, we show that comparing the genome-wide pattern of Rpd3 binding with gene expression and histone acetylation in the rpd3 Delta mutant strain reveals new sites of Rpd3 function.

Acetylation↗
PubMed2002

Microarray deacetylation maps determine genome-wide functions for yeast histone deacetylases.

Yeast contains a family of five related histone deacetylases (HDACs) whose functions are known at few genes. Therefore, we used chromatin immunoprecipitation and intergenic microarrays to generate genome-wide HDAC enzyme activity maps. Rpd3 and Hda1 deacetylate mainly distinct promoters and gene classes where they are recruited largely by novel mechanisms. Hda1 also deacetylates subtelomeric domains containing normally repressed genes that are used instead for gluconeogenesis, growth on carbon sources other than glucose, and adverse growth conditions. These domains have certain features of heterochromatin but are distinct from subtelomeric heterochromatin repressed by the deacetylase Sir2. Finally, Hos1/Hos3 and Hos2 preferentially affect ribosomal DNA and ribosomal protein genes, respectively. Thus, acetylation microarrays uncover the "division of labor" for yeast histone deacetylases.

Carrier Proteins↗