Beiying Qiu1,7, Xiaohe Shi2,7, Ee Tsin Wong1,7, Joy Lim2, Marco Bezzi1, Diana Low1, Qiling Zhou1, Semih Can Akıncılar1, Manikandan Lakshmanan1, Hannah L.F. Swa1, Jill Mae Lan Tham1, Jayantha Gunaratne1, Kenneth K. Y. Cheng3, Wanjin Hong1, Karen S. L. Lam3, Masahito Ikawa4, Ernesto Guccione1, Aimin Xu3,5, Weiping Han2,6* , Vinay Tergaonkar1,6*
1 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138673, Singapore;
2 Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), 138667, Singapore;
3 State Key Laboratory of Pharmaceutical Biotechnology,
5 Department of Medicine, The University of Hong Kong, Hong Kong, China;
4 University of Osaka, Osaka, 565-0871, Japan;
6 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore;
7 These authors contributed equally to this study.
* Co-first author
Published online in Cell Reports on 12 June 2014.
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, increased body weight/fat mass, along with impaired glucose tolerance and reduced insulin sensitivity, all of which are further exacerbated by high fat diet (HFD). Genome-wide ChIP-Sequcing (ChIP-Seq) identifies metabolism and insulin signaling as NUCKS targets. Importantly, NUCKS is down-regulated in individuals with high body mass index and in mice on HFD and conversely, its levels increase upon starvation. Taken together, 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.
Figure legend: Qiu, and colleagues report the identification of NUCKS, a novel protein that regulates transcription of genes like insulin receptor that mediate sensitivity to insulin signaling. The illustration depicts lean subjects opening chromatin (represented by the chest expander) around the genes regulating insulin signaling using NUCKS as a handle. Loss of NUCKS in obese subjects renders them insulin resistant due to their inability to turn on insulin signaling genes in tightly wound chromatin.
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