Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Histone H3 lysine 56 acetylation is linked to the core transcriptional network in human embryonic stem cells

ABSTRACT: Lysine 56 acetylation in the helical core of histone H3 opens yeast chromatin and enables histone gene transcription, DNA replication, DNA repair, and prevents epigenetic silencing. While K56Ac is globally abundant in yeast and flies its presence has been uncertain in mammals. We show here using mass spectrometry and genome wide analyses that K56Ac is present in human embryonic stem cells (hESCs) overlapping strongly at active and inactive promoters with the binding of the key regulators of pluripotency NANOG, SOX2 and OCT4. This includes also the canonical histone gene promoters and those for the hESC-specific microRNAs. K56Ac then relocates to developmental genes upon cellular differentiation. Thus K56Ac state more accurately reflects the epigenetic differences between hESCs and somatic cells than other active histone marks such as H3 K4 tri-methylation and K9 acetylation. These results suggest that K56Ac is involved in the human core transcriptional network of pluripotency. Genome wide location analysis ChIP-chip was performed in two human embryonic stem cell lines (HSF1 and HSF6) and two somatic cell lines (ARPE and BJ), for each of the following histone modifications: H3 K56Ac, H3 K9Ac, H3 K4me3 and H3 K27me3.

ORGANISM(S): Homo sapiens

SUBMITTER: Wei Xie

PROVIDER: E-GEOD-14749 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Histone h3 lysine 56 acetylation is linked to the core transcriptional network in human embryonic stem cells.

Xie Wei W Song Chunying C Young Nicolas L NL Sperling Adam S AS Xu Feng F Sridharan Rupa R Conway Anne E AE Garcia Benjamin A BA Plath Kathrin K Clark Amander T AT Grunstein Michael M

Molecular cell 20090201 4

Lysine 56 acetylation in the helical core of histone H3 opens yeast chromatin and enables histone gene transcription, DNA replication, and DNA repair and prevents epigenetic silencing. While K56Ac is globally abundant in yeast and flies, its presence has been uncertain in mammals. We show here using mass spectrometry and genome-wide analyses that K56Ac is present in human embryonic stem cells (hESCs), overlapping strongly at active and inactive promoters with the binding of the key regulators of ...[more]

PMID: 19250903

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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.

Dataset Information

Histone H3 lysine 56 acetylation is linked to the core transcriptional network in human embryonic stem cells

Publications

Histone h3 lysine 56 acetylation is linked to the core transcriptional network in human embryonic stem cells.

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