The research goal of Dr. Trivedi’s laboratory is to identify causal mechanisms of congenital cardiac and vascular diseases affecting human patients. Our discoveries have uncovered essential roles of chromatin-modifying enzymes and signaling pathways in the pathogenesis of human diseases such as Emberger syndrome - Lymphedema (The Journal of Clinical Investigation), Holt-Oram syndrome (Human Molecular Genetics), Hepatic cavernous hemangiomas (Journal of Experimental Medicine), Aortic stenosis (JBC), Epithelioid hemangioendothelioma (ATVB), Mitochondrial disease (Science Advances), Congenital heart disease (Developmental Cell, JBC), Craniofacial anomalies (Developmental Dynamics), and Hypertrophic cardiomyopathy (Nature Medicine). These discoveries have opened new areas of investigation, identified fundamental developmental processes, and contributed to a roadmap for novel therapies.
Emberger syndrome (Lymphedema) is a lymphatic anomaly, and it is responsible for considerable morbidity, with no current effective treatments. The underlying pathology is often defective lymphatic valve development leading to improper drainage of extravasated protein-rich fluid from the tissues. Recently we revealed how human genetic variants or mutations within evolutionarily conserved non-coding DNA elements alter recruitment of histone deacetylase 3 (Hdac3), thus modifying gene expression to cause lymphedema (The Journal of Clinical Investigation). Our study demonstrates that Hdac3 is essential for lymphatic valve development, thus lymphatic drainage in mice. Hdac3-deficient lymphatic valves exhibit reduced expression of Gata2, which is frequently mutated in patients with Emberger syndrome. In response to extracellular oscillatory shear stress (OSS), Hdac3 functions in a chromatin-dependent, but deacetylase-independent, manner to activate Gata2 expression within lymphatic endothelial cells (LECs), the building blocks of the mammalian lymphatic valves. Mechanistically, the transcription factors Tal1, Gata2, and Ets1/2 physically interacted with and recruited Hdac3 to the evolutionarily conserved (divergence ~350 million years ago) E-box–GATA–ETS composite element of a Gata2 intragenic enhancer in response to OSS. In turn, Hdac3 recruited histone acetyltransferase Ep300 to form an enhanceosome complex that promoted Gata2 expression. Interestingly, mutations within this conserved GATA2 intragenic enhancer reduce GATA2 expression and cause lymphedema (Emberger syndrome) in both humans and mice. These data challenge long-held assumptions that HDACs replace HATs to promote both histone deacetylation and repression of transcription.
Hepatic vascular cavernomas, the most common benign tumor of the liver, cause lethal complications such as hepatic rupture, consumption coagulopathy, and cardiac failure. Although Virchow and Frerichs described hepatic vascular cavernomas as a distinct clinical entity in the mid-1800s, their genetic etiology, molecular mechanism, and effective treatment remain undefined. Recently we identified gain-of-function mutations in KRAS or BRAF genes within liver endothelial cells as a causal mechanism for hepatic vascular cavernomas (Journal of Experimental Medicine). We identified gain-of-function mutations in KRAS or BRAF genes in pathological liver tissue samples from patients with hepatic vascular cavernomas. Mice expressing this human KRASG12D or BRAFV600E gain-of-function mutations in hepatic endothelial cells recapitulated the human hepatic vascular cavernoma phenotype of dilated sinusoidal capillaries with defective branching patterns. KRASG12D or BRAFV600E induced “zipper-like” contiguous expression of junctional proteins at sinusoidal endothelial cell-cell contacts, switching capillaries from branching to cavernous expansion. Pharmacological or genetic inhibition of the endothelial RAS–MAPK1 signaling pathway rescued hepatic vascular cavernoma formation in endothelial KRASG12D- or BRAFV600E-expressing mice. These results uncover a major cause of hepatic vascular cavernomas and provide a road map for their personalized treatment.
Our recent study identifies a causal relationship between Congenital Heart Disease (CHD), the most common developmental defect in children, and defective developmental energy generation (Science Advances). We demonstrated that two class I histone deacetylases, Hdac1 and Hdac2, silence cryptic transcription to promote mitochondrial function in developing murine hearts. Cryptic transcription is observed in lower organisms and mammalian cell lines, yet no reports describe cryptic transcription in a vertebrate system. This report is the first link between chromatin-modifying enzymes and cryptic transcription during vertebrate development and the first to link cryptic transcription and energy production during cardiogenesis.