PT  - JOURNAL ARTICLE
AU  - Valerio Bianchi
AU  - Geert Geeven
AU  - Nathan Tucker
AU  - Catharina R.E. Hilvering
AU  - Amelia W. Hall
AU  - Carolina Roselli
AU  - Matthew C. Hill
AU  - James F. Martin
AU  - Kenneth B. Margulies
AU  - Patrick T. Ellinor
AU  - Wouter de Laat
TI  - Detailed Regulatory Interaction Map of the Human Heart Facilitates Gene Discovery for Cardiovascular Disease
AID  - 10.1101/705715
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 705715
4099  - http://biorxiv.org/content/early/2019/07/17/705715.short
4100  - http://biorxiv.org/content/early/2019/07/17/705715.full
AB  - Most disease-associated variants identified by population based genetic studies are non-coding, which compromises finding causative genes and mechanisms. Presumably they interact through looping with nearby genes to modulate transcription. Hi-C provides the most complete and unbiased method for genome-wide identification of potential regulatory interactions, but finding chromatin loops in Hi-C data remains difficult and tissue specific data are limited. We have generated Hi-C data from primary cardiac tissue and developed a method, peakHiC, for sensitive and quantitative loop calling to uncover the human heart regulatory interactome. We identify complex CTCF-dependent and -independent contact networks, with loops between coding and non-coding gene promoters, shared enhancers and repressive sites. Across the genome, enhancer interaction strength correlates with gene transcriptional output and loop dynamics follows CTCF, cohesin and H3K27Ac occupancy levels. Finally, we demonstrate that intersection of the human heart regulatory interactome with cardiovascular disease variants facilitates prioritizing disease-causative genes.