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

Matthew C. Pahl, Claudia A. Doege, Kenyaita M. Hodge, Sheridan H. Littleton, Michelle E. Leonard, Sumei Lu, Rick Rausch, James A. Pippin, Maria Caterina Rosa, Alisha Basak, Jonathan P. Bradfield, Reza K. Hammond, Keith Boehm, Robert I. Berkowitz, Chiara Lasconi, Chun Su, Alessandra Chesi, Matthew E. Johnson, Andrew D. Wells, Benjamin F. Voight, Rudolph L. Leibel, Diana L. Cousminer and Struan F. A. Grant ()
Additional contact information
Matthew C. Pahl: Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
Claudia A. Doege: Columbia University Vagelos College of Physicians and Surgeons
Kenyaita M. Hodge: Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
Sheridan H. Littleton: Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
Michelle E. Leonard: Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
Sumei Lu: Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
Rick Rausch: Columbia University, Vagelos College of Physicians and Surgeons
James A. Pippin: Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
Maria Caterina Rosa: Columbia University, Vagelos College of Physicians and Surgeons
Alisha Basak: Columbia University, Vagelos College of Physicians and Surgeons
Jonathan P. Bradfield: Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
Reza K. Hammond: Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
Keith Boehm: Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
Robert I. Berkowitz: The University of Pennsylvania Perelman School of Medicine
Chiara Lasconi: Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
Chun Su: Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
Alessandra Chesi: Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
Matthew E. Johnson: Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
Andrew D. Wells: Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
Benjamin F. Voight: University of Pennsylvania
Rudolph L. Leibel: Division of Molecular Genetics (Pediatrics) and the Naomi Berrie Diabetes Center, Columbia University Vagelos College of Physicians and Surgeons
Diana L. Cousminer: Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
Struan F. A. Grant: Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-27001-4

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