ARID1a and Chromatin Landscape in Pulmonary Vascular Disease

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

PROJECT SUMMARY Pulmonary arterial hypertension (PAH) is a rare, chronic, and progressive pulmonary vascular disease leading to right ventricle failure and ultimately to death. Despite the available treatments and ongoing research efforts, there is currently no curative treatment against PAH or the pathological vascular remodeling. Current understanding of the dysregulation of chromatin in PAH pathogenesis remains limited. The SWItch/Sucrose Non- Fermentable (SWI/SNF) chromatin remodeling complexes control accessibility of chromatin to transcriptional and coregulatory machineries. The AT-rich interactive domain-containing protein 1a (ARID1a), a subunit of the SWI/SNF chromatin-remodeling complex, plays important roles in normal physiology and diseases. Homeostasis requires balanced action of ARID1a and EZH2, a histone methyltransferase, through chromatin-mediated gene expression. Yet, the role of ARID1a in PAH remains understudied. Given the various studies implicating ARID1a as a critical tumor suppressor, the objective of this proposal is to investigate the expression level of ARID1a and the link between ARID1A and EZH2 in pulmonary vascular smooth muscle cells (PASMCs) growth and dysfunction. The central hypothesis is that ARID1a loss impairs enhancer-mediated gene regulation and drives aberrant growth of PASMC in PAH through altered chromatin accessibility and/or DNA methylation via EZH2 (Fig. 1). The hypothesis is supported by preliminary data of the downregulation of ARID1a expression level in human and animal models of PAH. Importantly, ARID1a depletion using shRNA increased PASMC proliferation and increased EZH2 expression. Hence, the hypothesis will be tested by pursuing the following two specific aims: 1) Investigate the emerging roles of ARID1a in PASMC phenotype and the regulation of gene expression through EZH2 and targeted modulation of chromatin accessibility, and 2) Evaluate the effects of ARID1a-specific ablation in SMC and the intratracheal delivery of EZH2 inhibitors in ARID1aSMC-/- mice exposed to chronic hypoxia and Sugen conditions. The data generated from this proposal will advance our knowledge about the role of ARID1a in the phenotype of PASMC-driven pulmonary vascular disease, with implications for therapeutic interventions in PAH.