Abstract 115: Chromatin Microenvironments With Distinct Functionality During Cardiac Stress
| Autor: | Thomas M. Vondriska, Douglas J. Chapsky, Manuel Rosa-Garrido, Maximilian Cabaj, Elaheh Karbassi |
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| Rok vydání: | 2018 |
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| Zdroj: | Circulation Research. 123 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | Loss of the chromatin structural protein CTCF induces heart failure. Chromatin capture experiments (Hi-C), which detect genomic interactions, revealed global remodeling of chromatin structure after cardiac-specific depletion of CTCF or pressure overload (TAC). In the present study, we investigated epigenomic features (histone marks and DNA methylation) contributing to distinct behaviors of chromatin microenvironments. CTCF-KO or TAC induced gene expression changes mediated by a shift in compartmentalization between active and inactive chromatin (~4% of the genome). At the transcriptome level, genes significantly dysregulated in disease were involved in cardiac function ( e.g. , Mybpc3, Lmna , Hand2 ), chromatin structure ( e.g. , Hmgb2 , Rad21 ), and histone modification ( e.g. , Hdac4 , Mapk14, Foxo1 ). Our Hi-C data allowed us to correlate changes in gene expression with localization within the nucleus, showing efficient segregation of differentially expressed genes into specific neighborhoods with similar expression behavior. Analyses of histone marks in these neighborhoods reveal enrichment of activating and inhibiting marks, H3K9ac and H3K9me3, respectively, in the specialized chromatin environments associated with gene expression or silencing. DNA methylation studies showed that transcriptionally active neighborhoods tended to have unmethylated CpGs, while repressive environments were methylated. Our Hi-C data also showed how active environments positively influence the expression of the genes that physically interact with them. For example, 351 unique genes with interacting partner genes had increased H3K9ac after TAC, and their 3D interacting partners included 200 upregulated genes and 104 downregulated genes, demonstrating similar transcriptional behavior in areas with similar epigenomic features and anatomical distribution in the nucleus. Heart failure involves conserved structural reprogramming of these chromatin microenvironments. |
| Databáze: | OpenAIRE |
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