Transcriptional Regulation of ZNF638 in Thermogenic Cells by the cAMP Response Element Binding Protein in Male Mice

Abstract

Zinc finger factors are implicated in a variety of cellular processes, including adipose tissue differentiation and thermogenesis. We have previously demonstrated that zinc finger protein 638 (ZNF638) is a transcriptional coactivator acting as an early regulator of adipogenesis in vitro. In this study, we show, to our knowledge for the first time, that, in vivo, ZNF638 abounds selectively in mature brown and subcutaneous fat tissues and in fully differentiated thermogenic adipocytes. Furthermore, gene expression studies revealed that ZNF638 is upregulated by cAMP modulators in vitro and by cold exposure and by pharmacological stimulation of β-adrenergic signaling in vivo. In silico analysis of the upstream regulatory region of the ZNF638 gene identified two putative cAMP response elements within 500 bp of the ZNF638 transcription start site. Detailed molecular analysis involving EMSA and chromatin immunoprecipitation assays demonstrated that cAMP response element binding protein (CREB) binds to these cAMP response element regions of the ZNF638 promoter, and functional studies revealed that CREB is necessary and sufficient to regulate the levels of ZNF638 transcripts. Taken together, these results demonstrate that ZNF638 is selectively expressed in mature thermogenic adipocytes and tissues and that its induction in response to classic stimuli that promote heat generation is mediated via CREB signaling, pointing to a possible novel role of ZNF638 in brown and beige fat tissues.

USP7 mediates pathological hepatic de novo lipogenesis through promoting stabilization and transcription of ZNF638

“…These results suggest that USP7 not only stabilizes ZNF638 protein but also up-regulates ZNF638 mRNA. To elucidate the potential mechanism by which USP7 positively regulates the mRNA of ZNF638, we assessed CREB, a known transcription factor of ZNF638 25 with induction or inhibition of USP7 in SK-Hep1 cells. Importantly, the protein of CREB was markedly reduced via USP7 knockdown or P22077 administration, whereas increased by USP7 overexpression (Fig.…”

Transferrin Receptor Functionally Marks Thermogenic Adipocytes

“…Zinc finger protein family is one of the largest protein family. Various critical zinc finger proteins, including Prdm16, Znf638, Zfp423, etc., have been shown to play critical roles in mitochondrial and fat biology (Shao et al, 2016a,b;Kissig et al, 2017;Perie et al, 2019). Thus, further studies are warranted to understand the finely tuned functions of ion signaling in mitochondrial functionality and thermogenesis.…”

The Effect of FOXC2-AS1 on White Adipocyte Browning and the Possible Regulatory Mechanism

“…Fsk is a classical inductor of browning of adipocytes, which triggers cAMP production. Much progress has been made in elucidating the cAMP-regulated genes, including interferon regulatory factor 4 (46), bone morphogenic protein 7 (47), zinc finger protein 516 (48), and zinc finger protein 638 (49), which promotes the browning characteristics of white adipose with a more oxidative metabolic phenotype. In addition to encoding genes, adipose tissues-or adipocytes-derived lncRNA BATE10 (28) and Gm13133 (30) have also been demonstrated to be regulated by cAMP, showing a similar expression pattern with FOXC2-AS1.…”