NFIA determines the cis-effect of genetic variation on Ucp1 expression in murine thermogenic adipocytes

Yuta Hiraike; Shuichi Tsutsumi; Takahito Wada; Misato Oguchi; Kaede Saito; Masahiro Nakamura; Satoshi Ota; Michinori Koebis; Harumi Nakao; Atsu Aiba; Gaku Nagano; Haruya Ohno; Kenji Oki; Masayasu Yoneda; Takashi Kadowaki; Hiroyuki Aburatani; Hironori Waki; Toshimasa Yamauchi

doi:10.1016/j.isci.2022.104729

NFIA determines the cis-effect of genetic variation on Ucp1 expression in murine thermogenic adipocytes

iScience. 2022 Jul 7;25(8):104729. doi: 10.1016/j.isci.2022.104729. eCollection 2022 Aug 19.

Authors

Yuta Hiraike^{1

2}, Shuichi Tsutsumi³, Takahito Wada¹, Misato Oguchi¹, Kaede Saito¹, Masahiro Nakamura⁴, Satoshi Ota³, Michinori Koebis⁵, Harumi Nakao⁵, Atsu Aiba⁵, Gaku Nagano⁶, Haruya Ohno⁶, Kenji Oki⁶, Masayasu Yoneda⁶, Takashi Kadowaki^{1

7

8}, Hiroyuki Aburatani³, Hironori Waki^{1

9}, Toshimasa Yamauchi¹

Affiliations

¹ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan.
² Division for Health Service Promotion, the University of Tokyo, Tokyo 113-0033, Japan.
³ Genome Science and Medicine Laboratory, Research Center for Advanced Science and Technology, the University of Tokyo, Tokyo 153-8904, Japan.
⁴ Precision Health, Department of Bioengineering, Graduate School of Engineering, the University of Tokyo, Tokyo 113-8655, Japan.
⁵ Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan.
⁶ Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
⁷ Department of Prevention of Diabetes and Lifestyle-Related Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan.
⁸ Toranomon Hospital, Tokyo 105-8470, Japan.
⁹ Department of Diabetes and Endocrinology, Akita University Graduate School of Medicine, Akita 010-8543, Japan.

Abstract

Thermogenic 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 a cis-regulatory variant rs47238345 that is responsible for differential Ucp1 expression. The alternative T allele of rs47238345 at the Ucp1 -12kb enhancer in 129 facilitates the allele-specific binding of nuclear factor I-A (NFIA) to mediate allele-specific enhancer-promoter interaction and Ucp1 transcription. 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 a trans-acting regulator of Ucp1 in mice and humans. These results demonstrate the cis- and trans-acting effects of genetic variation on Ucp1 expression that underlie phenotypic diversity.

Keywords: Epigenetics; Molecular biology; Molecular physiology; Physiology.