To investigate the role of enhancer of zeste homolog (EZH) 1 and EZH2 in liver homeostasis, mice were generated that carried Ezh1 ^‐/‐ and EZH2 ^fl/fl alleles and an Alb‐ Cre transgene. Only the combined loss of EZH1 and EZH2 in mouse hepatocytes caused a depletion of global trimethylation on Lys 27 of histone H3 (H3K27me3) marks and the specific loss of over ~1900 genes at 3 mo of age. Ezh1 ^‐/‐ ,Ezh2 ^fl/fl Alb‐Cre mice exhibited progressive liver abnormalities manifested by the development of regenerative nodules and concomitant periportal fibrosis, inflammatory infiltration, and activation of A6‐positive hepatic progenitor cells at 8 mo of age. In response to chronic treatment with carbon tetrachloride, all experimental mice, but none of the controls ( n = 27 each), showed increased hepatic degeneration associated with liver dysfunction and reduced ability to proliferate. After two‐thirds partial hepatectomy, mutant mice ( n = 5) displayed increased liver injury and a blunted regenerative response. Genomewide analyses at 3 mo of age identified 51 genes that had lost H3K27me3 marks, and their expression was significantly increased. These genes were involved in regulation of cell survival, fibrosis, and proliferation. H3K27me3 levels and liver physiology were unaffected in mice lacking either EZH1 globally or EZH2 specifically in hepatocytes. This work demonstrates a critical redundancy of EZH1 and EZH2 in maintaining hepatic homeostasis and regeneration.—Bae, W. K., Kang, K., Yu, J. H., Yoo, K. H., Factor, V. M., Kaji, K., Matter, M., Thorgeirsson, S., Hennighausen, L. The methyltransferases enhancer of zeste homolog (EZH) 1 and EZH2 control hepatocyte homeostasis and regeneration. FASEB J. 29, 1653‐1662 (2015). www.fasebj.org

Tissue-specific transcription is critical for normal development, and abnormalities causing undesirable gene expression may lead to diseases such as cancer. Such highly organized transcription is controlled by enhancers with specific DNA sequences recognized by transcription factors. Enhancers are associated with chromatin modifications that are distinct epigenetic features in a tissue-specific manner. Recently, super-enhancers comprising enhancer clusters co-occupied by lineage-specific factors have been identified in diverse cell types such as adipocytes, hair follicle stem cells, and mammary epithelial cells. In addition, noncoding RNAs, named eRNAs, are synthesized at super-enhancer regions before their target genes are transcribed. Many functional studies revealed that super-enhancers and eRNAs are essential for the regulation of tissue-specific gene expression. In this review, we summarize recent findings concerning enhancer function in tissue-specific gene regulation and cancer development.

Lung diseases, such as pulmonary hypertension and pulmonary fibrosis, are life-threatening diseases and have common features of vascular remodeling. During progression, extracellular matrix protein deposition and dysregulation of proteolytic enzymes occurs, which results in vascular stiffness and dysfunction. Although vasodilators or anti-fibrotic therapy have been mainly used as therapy owing to these characteristics, their effectiveness does not meet expectations. Therefore, a better understanding of the etiology and new therapeutic approaches are needed. Endothelial cells (ECs) line the inner walls of blood vessels and maintain vascular homeostasis by protecting vascular cells from pathological stimuli. Chronic stimulation of ECs by various factors, including pro-inflammatory cytokines and hypoxia, leads to ECs undergoing an imbalance of endothelial homeostasis, which results in endothelial dysfunction and is closely associated with vascular diseases. Emerging studies suggest that endothelial to mesenchymal transition (EndMT) contributes to endothelial dysfunction and plays a key role in the pathogenesis of vascular diseases. EndMT is a process by which ECs lose their markers and show mesenchymal-like morphological changes, and gain mesenchymal cell markers. Despite the efforts to elucidate these molecular mechanisms, the role of EndMT in the pathogenesis of lung disease still requires further investigation. Here, we review the importance of EndMT in the pathogenesis of pulmonary vascular diseases and discuss various signaling pathways and mediators involved in the EndMT process. Furthermore, we will provide insight into the therapeutic potential of targeting EndMT.

Sumin Oh, Chaeun Oh, and Kyung Hyun Yoo. BMB Reports 2017;50:445-53. https://doi.org/10.5483/BMBRep.2017.50.9.108

Altered miRNA (miR) expression occurs in various diseases. However, the therapeutic effect of miRNAs in autosomal dominant polycystic kidney disease (ADPKD) is unclear. Genome‐wide analyses of miRNA expression and DNA methylation status were conducted to identify crucial miRNAs in end‐stage ADPKD. miR‐192 and ‐194 levels were down‐regulated with hypermethylation at these loci, mainly in the intermediate and late stages, not in the early stage, of cystogenesis, suggesting their potential impact on cyst expansion. Cyst expansion has been strongly associated with endothelial‐mesenchymal transition (EMT). Zinc finger E‐box‐binding homeobox‐2 and cadherin‐2, which are involved in EMT, were directly regulated by miR‐192 and ‐194. The therapeutic effect of miR‐192 and ‐194 in vivo and in vitro were assessed. Restoring these miRs by injection of precursors influenced the reduced size of cysts in Pkd 1 conditional knockout mice. miR‐192 and ‐194 may act as potential therapeutic targets to control the expansion and progression of cysts in patients with ADPKD.—Kim, D. Y., Woo, Y. M., Lee, S., Oh, S., Shin, Y., Shin, J.‐O., Park, E. Y., Ko, J. Y., Lee, E. J., Bok, J., Yoo, K. H., Park, J. H. Impact of miR‐192 and miR‐194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease. FASEB J. 33, 2870–2884 (2019). www.fasebj.org

Background: Increased Galectin 3‐binding protein (LGALS3BP) serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma (HCC). Considering the crucial role of transforming growth factor‐β1 (TGF‐β1) in the emergence of these diseases, the present study tested the hypothesis that LGALS3BP regulates the TGF‐β1 signaling pathway. Methods: The expression levels of LGALS3BP and TGFB1 were analyzed in patients with metabolic dysfunction‐associated steatohepatitis (MASH) and HCC. Multiple omics techniques, such as RNA‐sequencing, transposase‐accessible chromatin‐sequencing assay, and liquid chromatography‐tandem mass spectrometry proteomics, were used to identify the regulatory mechanisms for the LGALS3BP‐TGF‐β1 axis. The effects of altered TGF‐β1 signaling by LGALS3BP were investigated in conditional LGALS3BP ‐knockin and LGALS3BP ‐knockout mice. Results: In patients with MASH and HCC, the levels of LGALS3BP and TGFB1 exhibited positive correlations. Stimulation of LGALS3BP by the inflammatory cytokine interferon α in HCC cells or ectopic overexpression of LGALS3BP in hepatocytes promoted the expression levels of TGFB1. Aggravated fibrosis was observed in the livers of hepatocyte‐specific LGALS3BP ‐knockin mice, with increased TGFB1 levels. LGALS3BP directly bound to and assembled integrin αV, an integral mediator required for releasing active TGF‐β1 from extracellular latent complex with the rearranged F‐actin cytoskeleton. The released TGF‐β1 activated JunB transcription factor, which in turn promoted the TGF‐β1 positive feedback loop. LGALS3BP deletion in the hepatocytes downregulated TGF‐β1 signaling and CCl ₄ induced fibrosis. Moreover, LGALS3BP depletion hindered hepatocarcinogenesis by limiting the availability of fibrogenic TGF‐β1. Conclusion: LGALS3BP plays a crucial role in hepatic fibrosis and carcinogenesis by controlling the TGF‐β1 signaling pathway, making it a promising therapeutic target in TGF‐β1‐related diseases.