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

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-pro...

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Published in:iScience 2022-08, Vol.25 (8), p.104729
Main Authors: 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
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container_issue 8
container_start_page 104729
container_title iScience
container_volume 25
creator 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
description 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.
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subjects Epigenetics
Molecular biology
Molecular physiology
Physiology
title NFIA determines the cis-effect of genetic variation on Ucp1 expression in murinethermogenic adipocytes
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