Epigenetic reactivation of transcriptional programs orchestrating fetal lung development in human pulmonary hypertension

Prakash Chelladurai, Carsten Kuenne, Alice Bourgeois, Stefan Günther, Chanil Valasarajan, Anoop V. Cherian, Robbert J. Rottier, Charlotte Romanet, Andreas Weigert, Olivier Boucherat, Christina A. Eichstaedt, Clemens Ruppert, Andreas Guenther, Thomas Braun, Mario Looso, Rajkumar Savai, Werner Seeger, Uta Maria Bauer, Sébastien Bonnet, Soni Savai Pullamsetti*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Article numbereabe5407
JournalScience Translational Medicine
Volume14
Issue number648
DOIs
Publication statusPublished - 8 Jun 2022

Bibliographical note

Funding Information:
We would like to acknowledge the technical contributions of N. Wilker, J. Rostkovius, V. Golchert, U. Eule, and E. Bieniek. This work was funded by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation)-Projektnummer 268555672-SFB 1213, projects A01, A05, A10N, and B02 grants to S.S.P., U.-M.B., R.S., and T.B. and European Research Council (ERC) Consolidator Grant (866051 to S.S.P.). C.K., S.G., T.B., M.L., W.S., and S.S.P. are supported by Excellence Cluster ECCPS/CPI (Exc2026). In vivo experiments were performed in Canada and funded by CIHR and Canadian Heart Stroke Foundation grants to S.B. and O.B. A.B. is supported by FRQS scholarship.

Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fingerprint

Dive into the research topics of 'Epigenetic reactivation of transcriptional programs orchestrating fetal lung development in human pulmonary hypertension'. Together they form a unique fingerprint.

Cite this