2018
DOI: 10.7554/elife.35788
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A promoter interaction map for cardiovascular disease genetics

Abstract: Over 500 genetic loci have been associated with risk of cardiovascular diseases (CVDs); however, most loci are located in gene-distal non-coding regions and their target genes are not known. Here, we generated high-resolution promoter capture Hi-C (PCHi-C) maps in human induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (CMs) to provide a resource for identifying and prioritizing the functional targets of CVD associations. We validate these maps by demonstrating that promoters preferentiall… Show more

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Cited by 122 publications
(82 citation statements)
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“…Both mRNA and protein expression levels of PGC-1α were downregulated in differentiate CMs upon TKI exposure and, conversely, upregulated by overexpression of GATA4 (Figure 7D and Supplemental Figure 5E). Moreover, further integration of the current GATA4 ChIP-seq data with promoter-capture Hi-C data previously reported in analogous day 20 CMs 45 , we confirmed a direct interaction between the GATA4-binding site with the PPARGC1A promoter anchor in CMs, consistent with long-range enhancer-promoter regulation through DNA looping (Figure 7E). Given the important roles of PGC-1α in regulating mitochondrial biogenesis and functions, altogether, this demonstrates that GATA4 binds to a PPARGC1A -enhancer and directly influences the expression of PGC-1α, thereby controlling mitochondrial biogenesis and function at early stages.…”
Section: Resultssupporting
confidence: 87%
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“…Both mRNA and protein expression levels of PGC-1α were downregulated in differentiate CMs upon TKI exposure and, conversely, upregulated by overexpression of GATA4 (Figure 7D and Supplemental Figure 5E). Moreover, further integration of the current GATA4 ChIP-seq data with promoter-capture Hi-C data previously reported in analogous day 20 CMs 45 , we confirmed a direct interaction between the GATA4-binding site with the PPARGC1A promoter anchor in CMs, consistent with long-range enhancer-promoter regulation through DNA looping (Figure 7E). Given the important roles of PGC-1α in regulating mitochondrial biogenesis and functions, altogether, this demonstrates that GATA4 binds to a PPARGC1A -enhancer and directly influences the expression of PGC-1α, thereby controlling mitochondrial biogenesis and function at early stages.…”
Section: Resultssupporting
confidence: 87%
“…( E ) Visualization of long-range PPARGC1A promoter interactions in iPSC-derived cardiomyocytes confirms direct interaction between GATA4-binding site and PPARGC1A anchor region. Red loop specifies individual long-range interaction called between the GATA4 binding site coordinates and the associated anchor used to capture PPARGC1A promoter interactions in cardiomyocytes 45 .…”
Section: Resultsmentioning
confidence: 99%
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“…In many cases, however, the target gene for a regulatory element is not the nearest gene 35 and therefore, information about distal chromatin interactions can be useful in prioritizing candidate gene targets of variants identified in GWAS. To this end, we generated a promoter capture Hi-C map (pcHi-C) of a decidualized cell line, thus enriching for the identification of long-range chromatin interactions between promoters and distant regulatory elements [36][37][38] . We identified a total of 161,337 interactions, of which 53,211 were between promoters and distal regions of accessible chromatin assayed by ATAC-seq and ChIP-seq, suggestive of their regulatory role.…”
Section: Chromatin Interactions Aid In the Identification Of Target Gmentioning
confidence: 99%
“…To measure co-accessible enrichments for TFs and chromatin looping, pgl files were created by pairing together EZH2 and Suz12 peaks within 500bp of one another, and pgltools 50 was used to convert calls from CTCF ChIA-PET 34 in GM12878 and pHiC in iPSCs 33 to the pgl format. Next, pgltools intersect1D was used to find accessible sites at opposing anchors of loops, or at Ezh2 Suz12 pairs, and p-values were obtained from the co-accessibility analysis for enrichments.…”
Section: Co-accessibility Enrichment At Co-binding Tfs and Chromatin mentioning
confidence: 99%