Unknown,Transcriptomics,Genomics,Proteomics

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Nitric oxide regulates gene expression in cancers by controlling histone posttranslational modifications [PrimeView]

ABSTRACT: Dynamic changes in histone posttranslational modifications (PTMs) are important regulators of chromatin structure and gene transcription in both normal and disease settings. Herein, we describe a novel signaling mechanism of nitric oxide (â?¢NO) by demonstrating its ability to modulate gene expression via alteration of histone PTMs. Having established that â?¢NO exposure induced differential expression of approximately 6500 genes, we set out to determine if there was an epigenetic component to their regulation. â?¢NO exposure led to alterations in the global levels of acetyl and methyl modifications at numerous lysine residues on core histones H3 and H4. Residues H3K9me2/ac were examined further and determined to have differential distribution at various loci throughout the genome in response to â?¢NO. Changes in the enrichment levels of H3K9me2/ac at specific genes correlated with changes in the expression levels of their transcripts. Molecular mechanisms contributing to phenotypic outcomes in â?¢NO-associated cancers remain to be well understood since traditional modes of â?¢NO-signaling do not explain a large proportion of its impact on tumor cell behavior. Our results reveal that â?¢NO drives a significant amount of gene expression changes epigenetically by changing the distribution of numerous histone marks. Cultured cells were treated with 500uM DETA/NO to examine the effects of a physiologically relevant â?¢NO concentration on gene expression. A total of two untreated biological replicates and two â?¢NO-treated biological replicates were harvested. The untreated samples served as control against which comparisons were made to elucidate â?¢NO-mediated changes in the gene expression.

ORGANISM(S): Homo sapiens

SUBMITTER: Douglas Thomas

PROVIDER: E-GEOD-66322 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Both genetic and environmental factors are implicated in Type 1 Diabetes (T1D). Since environmental factors can trigger epigenetic changes, we hypothesized that variations in histone posttranslational modifications (PTMs) at the promoter/enhancer regions of T1D susceptible genes may be associated with T1D. We therefore evaluated histone PTM variations at known T1D susceptible genes in blood cells from T1D patients versus healthy non-diabetic controls, and explored their connections to T1D. We used the chromatin-immunoprecipitation-linked-to-microarray approach to profile key histone PTMs, including H3-lysine-4 trimethylation (H3K4me3), H3K27me3, H3K9me3, H3K9 acetylation (H3K9Ac) and H4K16Ac at genes within the T1D susceptible loci in lymphocytes, and H3K4me3, H3K9me2, H3K9Ac and H4K16Ac at the IDDM1 region in monocytes of T1D patients and healthy controls separately. We screened for potential variations in histone PTMs using computational methods to compare datasets from T1D and controls. Interestingly, we observed marked variations in H3K9Ac levels at the upstream regions of HLA-DRB1 and HLA-DQB1 within the IDDM1 locus in T1D monocytes relative to controls. Additional experiments with THP-1 monocytes demonstrated increased expression of HLA-DRB1 and HLA-DQB1 in response to interferon- and TNF-treatment that were accompanied by changes in H3K9Ac at the same promoter regions as that seen in the patient monocytes. These results suggest that the H3K9Ac status of HLA-DRB1 and HLA-DQB1, two genes highly associated with T1D, may be relevant to their regulation and transcriptional response towards external stimuli. Thus, the promoter/enhancer architecture and chromatin status of key susceptible loci could be important determinants in their functional association to T1D susceptibility. We evaluated histone PTM variations at known T1D susceptible genes in blood cells from T1D patients versus healthy non-diabetic controls, and explored their connections to T1D. We used the ChIP-chip approach to profile key histone PTMs, including histone H3K4me3, H3K27me3, H3K9me3, H3K9 acetylation (H3K9Ac) and H4K16Ac, at genes within the T1D susceptible loci in lymphocytes.

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Nitric oxide regulates gene expression in cancers by controlling histone posttranslational modifications [PrimeView]

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