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Genome-wide mapping of histone marks at single-nucleosome resolution

ABSTRACT: Histone post-translational modifications (PTM) encode much of genome's regulatory information. However, regular chromatin immunoprecipitation followed by sequencing (ChIP-seq) protocols trace histone PTM to genomic regions spanning several nucleosomes, making it difficult to study how different histone PTM combine within individual nucleosomes to regulate the genome. Here, we devised computational and statistical methods to map H3K4me3, H3K27Ac, H3K9me3, and H3K27me3 to individual nucleosomes using MNase digestion of chromatin coupled with ChIP-seq. A significant number of nucleosomes were marked by two or more of histone marks. Nucleosomes marked simultaneously by H3K4me3 and H3K27me3 were prevalent among bivalent domains compared to the genomic background whereas nucleosomes having the repressive marks H3K27me3 and H3K9me3 were enriched at the transcription staring site of highly active genes only if they were also co-localized with the activating mark H3K27Ac. Inclusion of alternatively spliced exons on the final mRNA is correlated with nucleosomes marked by H3K4me3, H3K27Ac, and H3K27me3, but is largely unaffected by nucleosomes marked by H3K9me3. Together, these findings reveal that combinatorial patterns of histone PTM within individual nucleosomes are fundamental to encode regulatory information.

ORGANISM(S): Mus musculus

PROVIDER: GSE73004 | GEO | 2018/09/14

REPOSITORIES: GEO

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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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Genome-wide mapping of histone marks at single-nucleosome resolution

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