A new publication in the Science Transitional Medicine journal outlines a study which assesses the effects of epigenetic reactivation of transcriptional genes on pulmonary remodelling and hypertension in pulmonary atrial hypertension (PAH) conditions. PAH is a rare disorder wherein arterial pressures within the lungs are chronically and progressively elevated, leading to vasostrutcure degeneration. It is thought to be idiopathic or inheritable with a survival rate of 34% after 5 years, although there has been significant progress in treating PAH in the past 20 years, current treatments do not prevent remodelling of the pulmonary vasculature.
Chelladurai et al. (2022) at the Max Planck Institute for Heart and Lung Research conducted a study which focused on the integration of RNA sequencing and chromatin immunoprecipitation into PAH-fibroblasts and smooth muscle cells which resulted in de-repression of transcriptional signatures for lung tissue remodelling. Silencing angiogenesis/developmental regulator genes TBX4 & 5, SOX9 and EP300 led to mesenchymal signature regression. Pharmaceutical compounds where also used to inhibit P300 and CREB-binding protein complex which led to a reduction in vascular remodelling and muscularisation of distal vessels, improving haemodynamic which otherwise may lead to further vessel damage.
Vascular remodelling in PAH conditions is thought to be triggered by transcriptional coactivation factors and chromatin alterations, persistent activation of phenotypes aggravate vascular remodelling/muscularisation and quickly progresses the condition. This experiment displayed reversible PAH progression in three in vivo rodent models and reduced muscularisation of vessels in human ex vivo models. Results suggest that reactivating developmental transcription factors through epigenetic dysregulation may be beneficial in treating the remodelling aspect of PAH.
Read the article available at: https://www.science.org/doi/10.1126/scitranslmed.abe5407
Prakash Chelladurai, Carsten Kuenne, Alice Bourgeoisstefan Günther, Chanil Valasarajananoop V. Cherianrobbert J. Rottier, Charlotte Romanet, Andreas Weigert, Olivier Boucheratchristina A. Eichstaedtclemens Ruppert, Andreas Guenther, Thomas Braun, Mario Looso, Rajkumar Savai, Werner Seeger, Uta-Maria Bauersébastien Bonnet, Soni Savai Pullamsetti. (2022). Epigenetic reactivation of transcriptional programs orchestrating fetal lung development in human pulmonary hypertension. Science Translational Medicine. Vol 14, Issue 648. DOI: 10.1126/scitranslmed.abe5407
