Browsing by UMass Chan Affiliation "Li-Weibo Institute for Rare Diseases Research"
Now showing items 1-2 of 2
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Histone deacetylases 1 and 2 silence cryptic transcription to promote mitochondrial function during cardiogenesisCryptic transcription occurs widely across the eukaryotic genome; however, its regulation during vertebrate development is not understood. Here, we show that two class I histone deacetylases, Hdac1 and Hdac2, silence cryptic transcription to promote mitochondrial function in developing murine hearts. Mice lacking Hdac1 and Hdac2 in heart exhibit defective developmental switch from anaerobic to mitochondrial oxidative phosphorylation (OXPHOS), severe defects in mitochondrial mass, mitochondrial function, and complete embryonic lethality. Hdac1/Hdac2 promotes the transition to OXPHOS by enforcing transcriptional fidelity of metabolic gene programs. Mechanistically, Hdac1/Hdac2 deacetylates histone residues including H3K23, H3K14, and H4K16 to suppress cryptic transcriptional initiation within the coding regions of actively transcribed metabolic genes. Thus, Hdac1/2-mediated epigenetic silencing of cryptic transcription is essential for mitochondrial function during early vertebrate development.
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Sustained Activation of Endothelial YAP1 Causes Epithelioid HemangioendotheliomaEpithelioid hemangioendothelioma, first described in early 1980s,is a rare malignant vascular neoplasm with significant morbidity and mortality. Approximately 50% of epithelioid hemangioendotheliomas exhibit intravascular endothelial growth, yet their cellular origin, pathogenesis, and effective treatment remain undefined. Here, we identified stable nuclear expression of endothelial YAP1 (Yes1-associated transcriptional regulator) in pathological tissue samples from patients with epithelioid hemangioendothelioma. Mice expressing stable nuclear form of YAP1 in endothelial cells recapitulated the human intravascular epithelioid hemangioendothelioma phenotype. Sustained YAP1 activity induced mitosis and aberrant expression of lymphatic and epithelioid genes in blood endothelial cells. These results show sustained activation of endothelial YAP1 as a causal mechanism for intravascular epithelioid hemangioendothelioma.
