Master splicing regulator MBNL1 shapes large transcriptomic changes that drive cellular differentiation during development. Here we demonstrate that MBNL1 is a suppressor of tumor dedifferentiation. We surveyedMBNL1expression in matched tumor/normal pairs across The Cancer Genome Atlas and found thatMBNL1was down-regulated in several common cancers. Down-regulation ofMBNL1predicted poor overall survival in breast, lung, and stomach adenocarcinomas and increased relapse and distant metastasis in triple-negative breast cancer. Down-regulation of MBNL1 led to increased tumorigenic and stem/progenitor-like properties in vitro and in vivo. A discrete set of alternative splicing events (ASEs) are shared betweenMBNL1-low cancers and embryonic stem cells including aMAP2K7∆exon2 splice variant that leads to increased stem/progenitor-like properties via JNK activation. Accordingly, JNK inhibition is capable of reversingMAP2K7∆exon2-driven tumor dedifferentiation in MBNL1-low cancer cells. Our work elucidates an alternative-splicing mechanism that drives tumor dedifferentiation and identifies biomarkers that predict enhanced susceptibility to JNK inhibition.

PPARγ2 is expressed almost exclusively in adipose tissue and plays a central role in adipogenesis. Despite intensive studies over the last 2 decades, the mechanism regulating the expression of the Pparg2 gene, especially the role of cis-regulatory elements, is still not completely understood. Here, we report a comprehensive investigation of the enhancer elements within the murine Pparg2 gene. Utilizing the combined techniques of sequence conservation analysis and chromatin marker examination, we identified a potent enhancer element that augmented the expression of a reporter gene under the control of the Pparg2 promoter by 20-fold. This enhancer element was first identified as highly conserved non-coding sequence 10 (CNS10) and was later shown to be enriched with the enhancer marker H3 K27 acetylation. Further studies identified a binding site for p300 as the essential enhancer element in CNS10. Moreover, p300 physically binds to CNS10 and is required for the enhancer activity of CNS10. The depletion of p300 by siRNA resulted in significantly impaired activation of Pparg2 at the early stages of 3T3-L1 adipogenesis. In summary, our study identified a novel enhancer element on the murine Pparg2 gene and suggested a novel mechanism for the regulation of Pparg2 expression by p300 in 3T3-L1 adipogenesis.

Over the past decade, the increasing prevalence of obesity and its associated metabolic disorders constitutes one of the most concerning healthcare issues for countries worldwide. In an effort to curb the increased mortality and morbidity derived from the obesity epidemic, various therapeutic strategies have been developed by researchers. In the recent years, advances in the field of adipocyte biology have revealed that the thermogenic adipose tissue holds great potential in ameliorating metabolic disorders. Additionally, epigenetic research has shed light on the effects of histone acetylation on adipogenesis and thermogenesis, thereby establishing the essential roles which histone acetyltransferases (HATs) and histone deacetylases (HDACs) play in metabolism and systemic energy homeostasis. In regard to the therapeutic potential of thermogenic adipocytes for the treatment of metabolic diseases, herein, we describe the current state of knowledge of the regulation of thermogenic adipocyte differentiation and adaptive thermogenesis through histone acetylation. Furthermore, we highlight how different HATs and HDACs maintain the epigenetic transcriptional network to mediate the pathogenesis of various metabolic comorbidities. Finally, we provide insights into recent advances of the potential therapeutic applications and development of HAT and HDAC inhibitors to alleviate these pathological conditions.

Differential gene isoform expression is a ubiquitous mechanism to enhance proteome diversity and maintain cell homeostasis. Mechanisms such as splicing that drive gene isoform variability are highly dynamic and responsive to changes in cell signaling pathways. Wnt/β-catenin signaling has profound effects on cell activity and cell fate and is known to modify several splicing events by altering the expression of individual splicing factors. However, a global assessment of how extensively Wnt signaling regulates splicing and other mechanisms that determine mRNA isoform composition in cancer is lacking. We used deep time-resolved RNA-seq in two independent in vivo Wnt-addicted tumor models during treatment with the potent Wnt inhibitor ETC-159 and examined Wnt regulated splicing events and splicing regulators. We found 1025 genes that underwent Wnt regulated variable exon usage leading to isoform expression changes. This was accompanied by extensive Wnt regulated changes in the expression of splicing regulators. Many of these Wnt regulated events were conserved in multiple human cancers, and many were linked to previously defined cancer-associated splicing quantitative trait loci. This suggests that the Wnt regulated splicing events are components of fundamental oncogenic processes. These findings demonstrate the wide-ranging effects of Wnt signaling on the isoform composition of the cell and provides an extensive resource of expression changes of splicing regulators and gene isoforms regulated by Wnt signaling.