Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits

• Published in: Nature communications Vol. 12; no. 1; p. 6749
• Main Authors: Pahl, Matthew C., Doege, Claudia A., Hodge, Kenyaita M., Littleton, Sheridan H., Leonard, Michelle E., Lu, Sumei, Rausch, Rick, Pippin, James A., De Rosa, Maria Caterina, Basak, Alisha, Bradfield, Jonathan P., Hammond, Reza K., Boehm, Keith, Berkowitz, Robert I., Lasconi, Chiara, Su, Chun, Chesi, Alessandra, Johnson, Matthew E., Wells, Andrew D., Voight, Benjamin F., Leibel, Rudolph L., Cousminer, Diana L., Grant, Struan F. A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.11.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 14/63; 45/22; 45/23; 45/91; 631/208/177; 631/208/200; Body weight; Cell Differentiation - genetics; Cell Line; Chromatin; Chromosome Mapping; Differentiation; Endocrine system; Gene Expression Regulation, Developmental; Gene mapping; Gene regulation; Gene Regulatory Networks; Genes; Genome-Wide Association Study; High resolution; Homeostasis; Human Embryonic Stem Cells - physiology; Humanities and Social Sciences; Humans; Hypothalamus; Hypothalamus - cytology; Hypothalamus - embryology; multidisciplinary; Multifactorial Inheritance; Neurons - physiology; Pathogenesis; Regulatory Elements, Transcriptional - genetics; Regulatory sequences; RNA-Seq; Science; Science (multidisciplinary); Stem cells
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27001-4

The hypothalamus regulates metabolic homeostasis by influencing behavior and endocrine systems. Given its role governing key traits, such as body weight and reproductive timing, understanding the genetic regulation of hypothalamic development and function could yield insights into disease pathogenesis. However, given its inaccessibility, studying human hypothalamic gene regulation has proven challenging. To address this gap, we generate a high-resolution chromatin architecture atlas of an established embryonic stem cell derived hypothalamic-like neuron model across three stages of in vitro differentiation. We profile accessible chromatin and identify physical contacts between gene promoters and putative cis-regulatory elements to characterize global regulatory landscape changes during hypothalamic differentiation. Next, we integrate these data with GWAS loci for various complex traits, identifying multiple candidate effector genes. Our results reveal common target genes for these traits, potentially affecting core developmental pathways. Our atlas will enable future efforts to determine hypothalamic mechanisms influencing disease susceptibility. Understanding the genetic regulation of hypothalamic function could yield insights into disease pathogenesis, but its inaccessibility has made this challenging. Here the authors present a high-resolution chromatin atlas of a hypothalamic-like neuron model across three stages of differentiation.