NFIA determines the cis-effect of genetic variation on Ucp1 expression in murinethermogenic 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
Affiliations
Yuta Hiraike
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan; Division for Health Service Promotion, the University of Tokyo, Tokyo 113-0033, Japan; Corresponding author
Shuichi Tsutsumi
Genome Science and Medicine Laboratory, Research Center for Advanced Science and Technology, the University of Tokyo, Tokyo 153-8904, Japan
Takahito Wada
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan
Misato Oguchi
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan
Kaede Saito
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan
Masahiro Nakamura
Precision Health, Department of Bioengineering, Graduate School of Engineering, the University of Tokyo, Tokyo 113-8655, Japan
Satoshi Ota
Genome Science and Medicine Laboratory, Research Center for Advanced Science and Technology, the University of Tokyo, Tokyo 153-8904, Japan
Michinori Koebis
Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
Harumi Nakao
Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
Atsu Aiba
Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
Gaku Nagano
Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
Haruya Ohno
Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
Kenji Oki
Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
Masayasu Yoneda
Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
Takashi Kadowaki
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan; Department of Prevention of Diabetes and Lifestyle-Related Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan; Toranomon Hospital, Tokyo 105-8470, Japan
Hiroyuki Aburatani
Genome Science and Medicine Laboratory, Research Center for Advanced Science and Technology, the University of Tokyo, Tokyo 153-8904, Japan; Corresponding author
Hironori Waki
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan; Department of Diabetes and Endocrinology, Akita University Graduate School of Medicine, Akita 010-8543, Japan; Corresponding author
Toshimasa Yamauchi
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan; Corresponding author
Summary: 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.
