title: NUCKS is a positive transcriptional regulator of insulin signaling.
abstract: Although much is known about the molecular players in insulin signaling, there is scant information about transcriptional regulation of its key components. We now find that NUCKS is a transcriptional regulator of the insulin signaling components, including the insulin receptor (IR). Knockdown of NUCKS leads to impaired insulin signaling in endocrine cells. NUCKS knockout mice exhibit decreased insulin signaling and increased body weight/fat mass along with impaired glucose tolerance and reduced insulin sensitivity, all of which are further exacerbated by a high-fat diet (HFD). Genome-wide ChIP-seq identifies metabolism and insulin signaling as NUCKS targets. Importantly, NUCKS is downregulated in individuals with a high body mass index and in HFD-fed mice, and conversely, its levels increase upon starvation. Altogether, NUCKS is a physiological regulator of energy homeostasis and glucose metabolism that works by regulating chromatin accessibility and RNA polymerase II recruitment to the promoters of IR and other insulin pathway modulators.
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore.
authors.forename: Beiying
authors.initials: B
authors.lastname: Qiu
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138667, Singapore.
authors.forename: Xiaohe
authors.initials: X
authors.lastname: Shi
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore.
authors.forename: Ee Tsin
authors.initials: ET
authors.lastname: Wong
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138667, Singapore.
authors.forename: Joy
authors.initials: J
authors.lastname: Lim
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore.
authors.forename: Marco
authors.initials: M
authors.lastname: Bezzi
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore.
authors.forename: Diana
authors.initials: D
authors.lastname: Low
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore.
authors.forename: Qiling
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore.
authors.forename: Semih Can
authors.initials: SC
authors.lastname: Akıncılar
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Lakshmanan
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore.
authors.forename: Hannah L F
authors.initials: HL
authors.lastname: Swa
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore.
authors.forename: Jill Mae Lan
authors.initials: JM
authors.lastname: Tham
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore.
authors.forename: Jayantha
authors.initials: J
authors.lastname: Gunaratne
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Hong Kong, China.
authors.forename: Kenneth K Y
authors.initials: KK
authors.lastname: Cheng
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore.
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Hong Kong, China.
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
authors.affiliation: University of Osaka, Osaka 565-0871, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Ikawa
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Guccione
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138667, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore. Electronic address: weiping_han@sbic.a-star.edu.sg.
authors.forename: Weiping
authors.initials: W
authors.lastname: Han
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore. Electronic address: vinayt@imcb.a-star.edu.sg.
authors.forename: Vinay
authors.initials: V
authors.lastname: Tergaonkar
mesh_terms: D000818:Animals; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D005947:Glucose; D007328:Insulin; D009687:Nuclear Proteins; D010750:Phosphoproteins; C426654:NUCKS1 protein, human; C000591522:Nucks1 protein, mouse