Dr. Chinmay M. Trivedi’s laboratory seeks to define causal mechanisms that drive congenital cardiac and vascular diseases in human patients. By integrating human genetics, patient-derived tissue analyses, and mechanistic studies in animal models, we have uncovered essential roles for chromatin-modifying enzymes and developmental signaling pathways in a broad spectrum of disorders, including Emberger syndrome–associated lymphedema (The Journal of Clinical Investigation), Noonan syndrome–associated chylothorax and lymphangiectasia (JCI Insight), Holt–Oram syndrome (Human Molecular Genetics), hepatic cavernous hemangiomas (Journal of Experimental Medicine), aortic valve stenosis (Journal of Biological Chemistry, JCI Insight), epithelioid hemangioendothelioma (ATVB), mitochondrial disease (Science Advances), congenital heart disease (Developmental Cell, Journal of Biological Chemistry), craniofacial anomalies (Developmental Dynamics), and hypertrophic cardiomyopathy (Nature Medicine). Collectively, these discoveries have revealed fundamental developmental processes and laid the groundwork for mechanism-informed therapeutic strategies.
Emberger syndrome–associated lymphedema is a lymphatic anomaly that causes substantial morbidity and currently lacks effective treatments. A central pathology is defective lymphatic valve development, leading to impaired drainage of protein-rich interstitial fluid. Our work demonstrated that histone deacetylase 3 is essential for lymphatic valve development and lymphatic drainage in mice, and that disease-associated human genetic variants within evolutionarily conserved non-coding DNA elements disrupt histone deacetylase 3 recruitment to key regulatory loci. In lymphatic endothelial cells exposed to extracellular oscillatory shear stress, histone deacetylase 3 activates Gata2 expression through a chromatin-dependent but deacetylase-independent mechanism. Mechanistically, Tal1, Gata2, and Ets1/2 recruit histone deacetylase 3 to a deeply conserved E-box–GATA–ETS composite element within a Gata2 intragenic enhancer, enabling histone deacetylase 3 to scaffold Ep300 and assemble an enhanceosome that drives Gata2 transcription. Notably, mutations within this conserved GATA2 enhancer reduce GATA2 expression and cause lymphedema in both humans and mice, challenging the long-standing assumption that histone deacetylases primarily function by antagonizing histone acetyltransferases to repress transcription.
Hepatic vascular cavernomas, the most common benign tumor of the liver, can lead to life-threatening complications including rupture, consumption coagulopathy, and cardiac failure, yet their genetic etiology and effective therapies have remained unclear. We identified endothelial gain-of-function mutations in KRAS or BRAF as a causal mechanism in human hepatic cavernous cavernoma tissue samples and established in vivo causality using mouse models expressing KRAS^G12D or BRAF^V600E specifically in hepatic endothelial cells. These mice recapitulated the human phenotype, including dilated sinusoidal capillaries with defective branching. Mechanistically, oncogenic endothelial KRAS or BRAF induced “zipper-like” continuous junctional protein organization at sinusoidal endothelial cell–cell contacts, shifting vascular architecture from normal branching morphogenesis to cavernous expansion. Importantly, pharmacologic or genetic inhibition of endothelial RAS–MAPK1 signaling prevented or rescued cavernoma formation, providing a clear roadmap for mechanism-based and potentially personalized treatment.
Congenital heart disease, the most common developmental defect in children, is increasingly recognized as a disorder in which impaired bioenergetics can be a primary driver rather than merely a consequence of malformation. Our work revealed a causal relationship between congenital heart disease and defective developmental energy generation by demonstrating that class I histone deacetylases Hdac1 and Hdac2 suppress cryptic transcription to protect mitochondrial function during heart development. While cryptic transcription has been described in lower organisms and cultured mammalian cells, our study provided the first evidence of cryptic transcription control by chromatin-modifying enzymes in a vertebrate developmental context and linked this regulatory layer directly to mitochondrial performance during cardiogenesis. These findings establish an epigenetic framework through which transcriptional fidelity supports metabolic homeostasis in the developing heart.
Aortic valve stenosis is a progressive and increasingly prevalent disease with no approved pharmacologic therapies to prevent or slow progression. In our JCI Insight (2025) study, we showed that histone deacetylase 3 preserves aortic valve structure and function by coordinating epigenetic control of mitochondrial gene programs and maintaining extracellular matrix integrity in valvular interstitial fibroblasts. Diseased regions of human stenotic valves exhibited increased H3K27 acetylation and reduced histone deacetylase 3 activity. Consistently, mice lacking histone deacetylase 3 in aortic valves developed aortic valve stenosis with disrupted collagen organization, increased H3K27 acetylation, and premature mortality. Mechanistically, histone deacetylase 3 loss activated nuclear hormone receptor–regulated mitochondrial programs, increased oxidative phosphorylation, and induced reactive oxygen species–mediated damage. Importantly, metformin treatment—via mitochondrial complex I inhibition, restored redox balance, preserved collagen architecture, and improved valve function in histone deacetylase 3–deficient mice. Supporting these mechanistic data, retrospective clinical analysis linked metformin use with lower prevalence and slower progression of aortic valve stenosis, highlighting mitochondrial dysfunction as a therapeutic target in noncalcific aortic valve disease.
Lymphangiectasia with chylothorax is a lymphatic disorder marked by pathological dilation of lymphatic vessels and frequently complicated by chylous effusions, respiratory failure, and high mortality in young patients. In our JCI Insight (2022) study, we identified sustained MAPK activation in lymphatic endothelial cells in pathological human tissue samples and established causality in vivo using a neonatal mouse model in which endothelial KRAS^G12D drives persistent MAPK signaling. These mice developed severe pulmonary and intercostal lymphangiectasia, chyle accumulation in the pleural space, and complete lethality. Mechanistically, pathological MAPK activation suppressed an Nfatc1-dependent genetic program essential for laminin interactions, collagen crosslinking, and anchoring fibril formation, leading to defective lymphatic basement membrane assembly. Pharmacologic inhibition of MAPK signaling with ravoxertinib restored nuclear localization of Nfatc1, improved basement membrane integrity, reversed lymphangiectasia and chyle accumulation, and improved survival, supporting a tractable, mechanism-based therapeutic strategy for this devastating lymphatic disease.