Oral Presentation 16th Asian Conference on Transcription 2019

Common SNPs and Cohesin Genes: Long Distance Compensatory Regulation Reveals Gene Hubs in Cohesinopathies (1141)

William Schierding 1 2 , Julia Horsfield 2 3 , Justin O'Sullivan 1 2
  1. Liggins Institute, University of Auckland, Auckland, New Zealand
  2. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
  3. Department of Pathology, Dunedin School of Medicine, The University of Otago, Dunedin, New Zealand

Intergenic and even intronic variants mark DNA elements that regulate distant genes. These spatial-regulatory connections are largely set during human development, when the cohesin complex plays a key role in genome organisation. Variation in cohesin subunits or regulators of cohesin (loading and unloading from chromosomes) has been associated with an overlapping spectrum of human syndromes known as cohesinopathies. Here we used a common SNP approach across each cohesin-associated gene locus: all SNPs with cis-eQTLs (nearby regulation) in the GTEx portal to one of the genes comprising the cohesin ring subunits (SMC1A, SMC1B, SMC3, STAG1, STAG2, STAG3, RAD21, REC8, and RAD21L1) or the cohesin-ring regulators (CTCF, WAPL, NIPBL, MAU2, PDS5A, PDS5B). For each SNP, distant, allele-specific regulatory connections were determined by Hi-C spatial connection and verified by significant regulatory evidence through GTEx eQTL (FDR < 0.05). This analysis revealed common themes of cohesin-relevant pathways (genome organization, cell cycle, and DNA damage/repair), highlighting hubs of genes co-regulated in cohesinopathies. For example, SNPs in the RAD21L1 locus connect to RFC3 and KIF18A, which regulate cell cycle (GO:0007049). Long distance eQTLs originating from the MAU2 locus target ERCC1, ZBTB46, and ZNF790. Collectively, these results demonstrate the impacts of genetic variation on the coordinated expression of cohesin and functionally related genes. This highlights co-expressed genes that represent additional targets that may help improve our understanding of the pleiotropic impacts associated with cohesinopathies.