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

Chelladurai, P., Kuenne, C., Bourgeois, A., Guenther, S., Valasarajan, C., Cherian V, A., et al. (2022). Epigenetic reactivation of transcriptional programs orchestrating fetal lung development in human pulmonary hypertension. SCIENCE TRANSLATIONAL MEDICINE, 14(648): eabe5407. doi:10.1126/scitranslmed.abe5407.

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Chelladurai, Prakash1, Author              
Kuenne, Carsten2, Author              
Bourgeois, Alice, Author
Guenther, Stefan3, Author              
Valasarajan, Chanil1, Author              
Cherian V, Anoop4, Author              
Rottier, Robbert J., Author
Romanet, Charlotte, Author
Weigert, Andreas, Author
Boucherat, Olivier, Author
Eichstaedt, Christina A., Author
Ruppert, Clemens, Author
Guenther, Andreas, Author
Braun, Thomas3, Author              
Looso, Mario2, Author              
Savai, Rajkumar1, Author              
Seeger, Werner1, Author              
Bauer, Uta-Maria, Author
Bonnet, Sebastien, Author
Pullamsetti, Soni Savai1, Author              
Affiliations:
1Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              
2Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591704              
3Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591695              
4Developmental Genetics, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591697              

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 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.

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 Dates: 2022-06-08
 Publication Status: Published online
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Title: SCIENCE TRANSLATIONAL MEDICINE
Source Genre: Journal
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Pages: - Volume / Issue: 14 (648) Sequence Number: eabe5407 Start / End Page: - Identifier: ISSN: 1946-6234