RT Journal Article
SR Electronic
T1 Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.06.146951
DO 10.1101/2020.07.06.146951
A1 Matthew C. Pahl
A1 Claudia A. Doege
A1 Kenyaita M. Hodge
A1 Sheridan H. Littleton
A1 Michelle E. Leonard
A1 Sumei Lu
A1 Rick Rausch
A1 James A. Pippin
A1 Jonathan P. Bradfield
A1 Reza K. Hammond
A1 Keith Boehm
A1 Robert I. Berkowitz
A1 Chiara Lasconi
A1 Chun Su
A1 Alessandra Chesi
A1 Matthew E. Johnson
A1 Andrew D. Wells
A1 Benjamin F. Voight
A1 Rudolph L. Leibel
A1 Diana L. Cousminer
A1 Struan F.A. Grant
YR 2020
UL http://biorxiv.org/content/early/2020/07/06/2020.07.06.146951.abstract
AB The hypothalamus regulates metabolic homeostasis by influencing behavior, energy utilization and endocrine systems. Given its role governing health-relevant traits, such as body weight and reproductive timing, understanding the genetic regulation of hypothalamic development and function should yield insights into these traits and diseases. However, given its inaccessibility, studying human hypothalamic gene regulation has proven challenging. To address this gap, we generated a chromatin architecture atlas of an established embryonic stem cell (ESC)-derived hypothalamic-like neuron (HN) model across three stages of in vitro differentiation. We profiled accessible chromatin and identified physically interacting contacts between gene promoters and their putative cis-regulatory elements (cREs) to characterize changes in the gene regulatory landscape during hypothalamic differentiation. Next, we integrated these data with GWAS loci for multiple traits and diseases enriched for heritability in these cells, identifying candidate effector genes and cREs impacting transcription factor binding. Our results reveal common target genes for these traits, potentially identifying core hypothalamic developmental pathways. Our atlas will enable future efforts to determine precise mechanisms underlying hypothalamic development with respect to specific disease pathogenesis.Competing Interest StatementThe authors have declared no competing interest.