A promoter interaction map for cardiovascular disease genetics

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...

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Veröffentlicht in:bioRxiv
Hauptverfasser: Montefiori, Lindsey E, Sobreira, Debora R, Sakabe, Noboru J, Aneas, Ivy, Joslin, Amelia C, Hansen, Grace T, Bozek, Grazyna, Moskowitz, Ivan P, Mcnally, Elizabeth M, Nobrega, Marcelo A
Format: Paper
Sprache:Englisch
Veröffentlicht: Cold Spring Harbor Cold Spring Harbor Laboratory Press 08.06.2018
Cold Spring Harbor Laboratory
Ausgabe:1.1
Schlagworte:
Cardiomyocytes
Cardiovascular diseases
Chromatin
Gene expression
Gene mapping
Genetics
Pluripotency
Single-nucleotide polymorphism
Stem cells
ISSN:2692-8205, 2692-8205
Online-Zugang:Volltext
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Zusammenfassung: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 preferentially contact distal sequences enriched for tissue-specific transcription factor motifs and are enriched for chromatin marks that correlate with dynamic changes in gene expression. Using the CM PCHi-C map, we linked 1,999 CVD-associated SNPs to 347 target genes. Remarkably, more than 90% of SNP-target gene interactions did not involve the nearest gene, while 40% of SNPs interacted with at least two genes, demonstrating the importance of considering long-range chromatin interactions when interpreting functional targets of disease loci.
Bibliographie:SourceType-Working Papers-1
ObjectType-Working Paper/Pre-Print-1
content type line 50
ISSN:2692-8205
2692-8205
DOI:10.1101/340869