摘要：SummaryThermogenic brown and beige adipocytes counteract obesity by enhancing energy dissipation via uncoupling protein-1 (Ucp1). However, the effect of genetic variation on these cells, a major source of disease susceptibility, has been less well studied. Here we examined beige adipocytes from obesity-prone C57BL/6J (B6) and obesity-resistant 129X1/SvJ (129) mouse strains and identified acis-regulatory variant rs47238345 that is responsible for differential Ucp1 expression. The alternative T allele of rs47238345 at theUcp1-12kb enhancer in 129 facilitates the allele-specific binding of nuclear factor I-A (NFIA) to mediate allele-specific enhancer-promoter interaction andUcp1transcription. Furthermore, CRISPR-Cas9/Cpf1-mediated single nucleotide polymorphism (SNP) editing of rs47238345 resulted in increased Ucp1 expression. We also identified Lim homeobox protein 8 (Lhx8), whose expression is higher in 129 than in B6, as atrans-acting regulator of Ucp1 in mice and humans. These results demonstrate thecis- andtrans-acting effects of genetic variation on Ucp1 expression that underlie phenotypic diversity.Graphical abstractDisplay OmittedHighlights•NFIA in adipocytes determines Ucp1 expression between obesity-prone and -resistant mouse strains•Allele-specific binding of NFIA at theUcp1-12kb enhancer mediates differential Ucp1 expression•Editing of a SNP at the Ucp1 -12kb enhancer is sufficient to increase Ucp1 in obesity-prone strainPhysiology; Molecular physiology; Molecular biology; Epigenetics
