Thursday, June 5, 2025
6/5/2025
The Chromatin Remodeling Factor ARID1a and the Epigenetic Landscape In Pulmonary Arterial Hypertension - PROJECT SUMMARY Pulmonary arterial hypertension (PAH is a rare, progressive, incurable, and fatal cardiopulmonary 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 pathological vascular remodeling. Changes in chromatin that can influence the epigenetic regulation of many genes and their functional consequences on vascular remodeling in PAH are poorly understood. The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes control the accessibility of chromatin to transcriptional and coregulatory machinery. The AT-rich interactive domain-containing protein 1a (ARID1a), a subunit of the SWI/SNF chromatin-remodeling complex, plays key roles in normal physiology and diseases. The functional implications of ARID1a deficiency are dependent on its downstream transcriptional consequences, which can be altered by other epigenetic transcriptional regulators in the specific cellular context. Homeostasis requires balanced action of ARID1a and the Enhancer of Zeste Homolog2 (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 PASMCs in PAH through altered chromatin accessibility and/or DNA methylation via EZH2. The hypothesis is supported by preliminary data of a significant reduction of ARID1a expression level in PAH human and animal models of PAH. Importantly, ARID1a depletion increases PASMC proliferation and increases EZH2 expression. Hence, the hypothesis will be tested by pursuing the following three specific aims: 1) Investigate the function of ARID1A in PASMC phenotype, and the central role of ARID1a in the chromatin dynamics and the regulation of gene expression in PASMCs; 2) Evaluate the impact of SMC conditional ARID1a ablation in the pathogenesis of PAH; and 3) Assess the effectiveness of the combination therapy of AAV2.5/ARID1a with EZH2 inhibitors in the context of severe rat models of PAH. 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 potential therapeutic interventions in PAH.
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