LAUSR

Phenotypic alterations in resident vascular cells contribute to the vascular remodeling process in diseases such as pulmonary (arterial) hypertension [P(A)H]. How the molecular interplay between transcriptional coactivators, transcription factors (TFs), and chromatin state alterations facilitate the maintenance of persistently activated cellular phenotypes that consequently aggravate vascular remodeling processes in PAH remains poorly explored. RNA sequencing (RNA-seq) in pulmonary artery fibroblasts (FBs) from adult human PAH and control lungs revealed 2460 differentially transcribed genes. Chromatin immunoprecipitation sequencing (ChIP-seq) revealed extensive differential distribution of transcriptionally accessible chromatin signatures, with 4152 active enhancers altered in PAH-FBs. Integrative analysis of RNA-seq and ChIP-seq data revealed that the transcriptional signatures for lung morphogenesis were epigenetically derepressed in PAH-FBs, including coexpression of T-box TF 4 (TBX4), TBX5, and SRY-box TF 9 (SOX9), which are involved in the early stages of lung development. These TFs were expressed in mouse fetuses and then repressed postnatally but were maintained in persistent PH of the newborn and reexpressed in adult PAH. Silencing of TBX4, TBX5, SOX9, or E1A-associated protein P300 (EP300) by RNA interference or small-molecule compounds regressed PAH phenotypes and mesenchymal signatures in arterial FBs and smooth muscle cells. Pharmacological inhibition of the P300/CREB-binding protein complex reduced the remodeling of distal pulmonary vessels, improved hemodynamics, and reversed established PAH in three rodent models in vivo, as well as reduced vascular remodeling in precision-cut tissue slices from human PAH lungs ex vivo. Epigenetic reactivation of TFs associated with lung development therefore underlies PAH pathogenesis, offering therapeutic opportunities. Description Aberrant epigenetic reactivation of developmental transcription factors underlies the pathogenesis of pulmonary hypertension. Deactivating developmental reactivation Pulmonary arterial hypertension (PAH) is a fatal disease, and current treatments do not restore vascular structure. Here, Chelladurai and colleagues integrated RNA sequencing and chromatin immunoprecipitation sequencing data from PAH pulmonary artery fibroblasts, revealing derepression of transcriptional signatures for lung morphogenesis. Silencing of TBX4, TBX5, and SOX9, as well as EP300, a regulator of developmental transcription factor expression, led to regression of mesenchymal signatures, and inhibition of the P300/CREB-binding protein complex using pharmacological compounds reduced vascular remodeling in precision-cut lung tissue slices. In three rat models of PAH, these compounds improved hemodynamics and reduced the muscularization of the distal pulmonary arteries, suggesting that controlling the epigenetic dysregulation of developmental transcription factors may be beneficial in this disease.