Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Histone H3 Ser10 phosphorylation in hpr1-101

ABSTRACT: R-loops are transcription by-products that may constitute a threat to genome integrity.We previously show in Saccharomyces cerevisiae that R-loops are tightly and specifically linked with histone H3-Ser10 phosphorylation (H3S10P), a mark of chromatin condensation. Here we analyse the hpr1-101 mutant. A point mutation that impairs transcription and mRNP biogenesis without increasing recombination. Importantly, ChIP-chip analyses reveal a clear H3S10P does not accumulate at the pericentromeric chromatin during the G1-phase of the cell cycle but during S-phase in non-accumulating R-loop hpr1-101. ChIP-chip studies were perfomed with antibodies against Histone H3 and the phosphorylated Histone H3 at Serine10 in the yeast S. cerevisiae.

ORGANISM(S): Saccharomyces cerevisiae

SUBMITTER: AndrÃ©s Aguilera

PROVIDER: E-GEOD-50110 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Epigenetic deregulation plays a critical role in the pathogenesis of Acute Myeloid Leukemia. But changes in histone modification patterns at the epigenome level still remain largely unknown. Here, we analyzed alterations of histone H3 acetylation patterns in a large number of patients with AML compared to CD34+ progenitor cells. Using ChIP-Chip assays, we demonstrate that AML blasts exhibit significant changes in Histone H3 acetylation levels at more than 1000 genomic loci. Importantly, at core promoter regions losses of H3 acetlyation levels prevailed which suggested that a large number of genes is epigenetically silenced in AML. The validation of identified genes led to the discovery of Peroxiredoxin 2 (PRDX2) as a potential tumor suppressor gene in AML. Peroxiredoxin-2 (PRDX2) was silenced in most AML patients by decreased Histone H3 acetylation and in almost 20% by promoter DNA hypermethylation. Low protein expression of the antioxidant PRDX2 gene was clinically associated with a poor prognosis in AML patients. Functionally, PRDX2 acted as an inhibitor of myeloid cell growth by reducing levels of reactive oxygen species generated in response to cytokines. A high level of PRDX2 expression inhibited myc-induced murine leukemogenesis whereas loss of PRDX2 increased myeloid cell proliferation and accelerated myc-induced leukemogenesis. Taken together, we identify widespread loss of Histone H3 acetylation at core promoter regions as a signature of AML blasts. Epigenome wide analyses of histone H3 acetylation led to the identification of PRDX2 as an epigenetically silenced growth suppressor that contributed to the malignant phenotype in AML. Blasts from patients with AML (n=72) were obtained at the time of diagnosis (in a few cases at first relapse). CD34+ progenitor cells (n=17) and white blood cells (n=16) were used as control samples. Immunoprecipitations were performed for anti-acetylated Histone H3. Chromatin-IPs were amplified using ligation mediated PCR and labeled using Cy3 coupled to incorporated amino-allyl-UTP. Common reference DNA consisting of a mixture of genomic DNA from AML patients was prepared, amplified and labeled in a similar way with Cy5.

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Histone H3 Ser10 phosphorylation in hpr1-101

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