Zbtb7b engages the long noncoding RNA Blnc1 to drive brown and beige fat development and thermogenesis

Abstract

Brown and beige adipocytes convert chemical energy into heat through uncoupled respiration to defend against cold stress. Beyond thermogenesis, brown and beige fats engage other metabolic tissues via secreted factors to influence systemic energy metabolism. How the protein and long noncoding RNA (lncRNA) regulatory networks act in concert to regulate key aspects of thermogenic adipocyte biology remains largely unknown. Here we developed a genome-wide functional screen to interrogate the transcription factors and cofactors in thermogenic gene activation and identified zinc finger and BTB domain-containing 7b (Zbtb7b) as a potent driver of brown fat development and thermogenesis and cold-induced beige fat formation. Zbtb7b is required for activation of the thermogenic gene program in brown and beige adipocytes. Genetic ablation of Zbtb7b impaired cold-induced transcriptional remodeling in brown fat, rendering mice sensitive to cold temperature, and diminished browning of inguinal white fat. Proteomic analysis revealed a mechanistic link between Zbtb7b and the lncRNA regulatory pathway through which Zbtb7b recruits the brown fat lncRNA 1 (Blnc1)/heterogeneous nuclear ribonucleoprotein U (hnRNPU) ribonucleoprotein complex to activate thermogenic gene expression in adipocytes. These findings illustrate the emerging concept of a protein-lncRNA regulatory network in the control of adipose tissue biology and energy metabolism.

hnRNPU/TrkB Defines a Chromatin Accessibility Checkpoint for Liver Injury and Nonalcoholic Steatohepatitis Pathogenesis

“…However, the exact residues, their upstream kinases, and the effects of hnRNPU phosphorylation on its biological functions remain currently unknown. Previous studies have demonstrated that hnRNPU interacts with a number of nuclear proteins including heterochromatin protein 1 alpha, the transcription factor Zbtb7b, and the long noncoding RNA Blnc1 . It is likely that regulation of these hnRNPU‐interacting factors may also underlie its effects on chromatin structure in response to physiological and pathophysiological stimuli.…”

“…Previous studies have demonstrated that hnRNPU interacts with a number of nuclear proteins including heterochromatin protein 1 alpha, the transcription factor Zbtb7b, and the long noncoding RNA Blnc1. (21,42,43) It is likely that regulation of these hnRNPU-interacting factors may also underlie its effects on chromatin structure in response to physiological and pathophysiological stimuli. Unlike transcriptional coactivators and repressors, the effects of hnRNPU inactivation on chromatin accessibility appeared to be bidirectional, suggesting that hnRNPU acts in a context-dependent manner to influence hepatic gene expression.…”

The how and why of lncRNA function: An innate immune perspective

“…If a candidate is lowly expressed, one can exogenously introduce a biotinylated form of the lncRNA using the RNA pull-down method, which we have successfully used to identify binding partners for lincRNA-Cox2. This has been performed for many lncRNAs [42,202,203].…”

Systems-Genetics-Based Inference of a Core Regulatory Network Underlying White Fat Browning

“…Adding further confidence to the derived gene regulatory network, multiple of its less established member genes have been experimentally validated in recent studies. For example, ZBTB7B, which is linked to M1 in our network, has been reported as a potent driver of brown fat development and thermogenesis and cold-induced brite adipocytes formation (Li et al, 2017a). Multiple genes in M3, such as HOXC10, P53, NR2C2, SRF, MEF2C, and NR2F2 have been shown to negatively regulate Ucp1 (Kang et al, 2011;Li et al, 2009;Ng et al, 2017).…”