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Regulation of early adipose commitment by Zfp521.

ABSTRACT: While there has been significant progress in determining the transcriptional cascade involved in terminal adipocyte differentiation, less is known about early events leading to lineage commitment and cell fate choice. It has been recently discovered that zinc finger protein 423 (Zfp423) is an early actor in adipose determination. Here, we show that a close paralog of Zfp423, Zfp521, acts as a key regulator of adipose commitment and differentiation in vitro and in vivo. Zfp521 exerts its actions by binding to early B cell factor 1 (Ebf1), a transcription factor required for the generation of adipocyte progenitors, and inhibiting the expression of Zfp423. Overexpression of Zfp521 in cells greatly inhibits adipogenic potential, whereas RNAi-mediated knock-down or genetic ablation of Zfp521 enhances differentiation. In addition, Zfp521⁻/⁻ embryos exhibit increased mass of interscapular brown adipose tissue and subcutaneous white adipocytes, a cell autonomous effect. Finally, Ebf1 participates in a negative feedback loop to repress Zfp521 as differentiation proceeds. Because Zfp521 is known to promote bone development, our results suggest that it acts as a critical switch in the commitment decision between the adipogenic and osteogenic lineages.

SUBMITTER: Kang S

PROVIDER: S-EPMC3507953 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Regulation of early adipose commitment by Zfp521.

Kang Sona S Akerblad Peter P Kiviranta Riku R Gupta Rana K RK Kajimura Shingo S Griffin Michael J MJ Min Jie J Baron Roland R Rosen Evan D ED

PLoS biology 20121127 11

While there has been significant progress in determining the transcriptional cascade involved in terminal adipocyte differentiation, less is known about early events leading to lineage commitment and cell fate choice. It has been recently discovered that zinc finger protein 423 (Zfp423) is an early actor in adipose determination. Here, we show that a close paralog of Zfp423, Zfp521, acts as a key regulator of adipose commitment and differentiation in vitro and in vivo. Zfp521 exerts its actions ...[more]

PMID: 23209378

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Project description:BackgroundCell differentiation during development is orchestrated by precisely coordinated gene expression programs. While some regulatory mechanisms are well understood, there is a significant room to explore unresolved aspects of lineage choice and cell-fate decisions, as many events in these processes are still not fully elucidated. Given that, gene expression is influenced not only by transcriptional control but also by post-transcriptional events. Here, we described the presence of post-transcriptional regulation on gene expression during lineage commitment across all three embryonic germ layers. We employed monolayer differentiation protocols to map early transcriptional and post-transcriptional events in human embryonic stem cell specification. This approach included obtaining representative populations from the three germ layers, followed by sequencing of both polysome-bound and total RNAs.ResultsWe characterized our model by its unique expression profile and the presence of specific markers for each differentiation. RNA sequencing revealed a consistent pattern of gene upregulated and downregulated when comparing the transcriptome and translatome during the differentiation of all three germ layers. By comparing these datasets, we identified genes subjected to post-transcriptional regulation in all germ layer differentiations and categorized the nature of this regulation. GO analysis demonstrated that polysome profiling serves as a complementary technique, capturing nuances that may be overlooked when analyzing only the transcriptome. Finally, we directly compared the transcriptome and translatome to identify genes actively recruited to the translation machinery, uncovering unique features specific to each germ layer.ConclusionsSubstantial post-transcriptional modulation was found during germ layer commitment, emphasizing the translatome potency in capturing nuanced gene expression regulation. These findings highlight the post-transcriptional regulation's critical role in early embryonic development, offering new insights into the molecular mechanisms of cell differentiation.

Project description:ObjectiveIncreasing adaptive thermogenesis by stimulating browning in white adipose tissue is a promising method of improving metabolic health. However, the molecular mechanisms underlying this transition remain elusive. Our study examined the molecular determinants driving the differentiation of precursor cells into thermogenic adipocytes.MethodsIn this study, we conducted temporal high-resolution proteomic analysis of subcutaneous white adipose tissue (scWAT) after cold exposure in mice. This was followed by loss- and gain-of-function experiments using siRNA-mediated knockdown and CRISPRa-mediated induction of gene expression, respectively, to evaluate the function of the transcriptional regulator Y box-binding protein 1 (YBX1) during adipogenesis of brown pre-adipocytes and mesenchymal stem cells. Transcriptomic analysis of mesenchymal stem cells following induction of endogenous Ybx1 expression was conducted to elucidate transcriptomic events controlled by YBX1 during adipogenesis.ResultsOur proteomics analysis uncovered 509 proteins differentially regulated by cold in a time-dependent manner. Overall, 44 transcriptional regulators were acutely upregulated following cold exposure, among which included the cold-shock domain containing protein YBX1, peaking after 24 h. Cold-induced upregulation of YBX1 also occurred in brown adipose tissue, but not in visceral white adipose tissue, suggesting a role of YBX1 in thermogenesis. This role was confirmed by Ybx1 knockdown in brown and brite preadipocytes, which significantly impaired their thermogenic potential. Conversely, inducing Ybx1 expression in mesenchymal stem cells during adipogenesis promoted browning concurrent with an increased expression of thermogenic markers and enhanced mitochondrial respiration. At a molecular level, our transcriptomic analysis showed that YBX1 regulates a subset of genes, including the histone H3K9 demethylase Jmjd1c, to promote thermogenic adipocyte differentiation.ConclusionOur study mapped the dynamic proteomic changes of murine scWAT during browning and identified YBX1 as a novel factor coordinating the genomic mechanisms by which preadipocytes commit to brite/beige lineage.

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Regulation of early adipose commitment by Zfp521.

Publications

Regulation of early adipose commitment by Zfp521.

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