title: Transcription factors, transcriptional coregulators, and epigenetic modulation in the control of pulmonary vascular cell phenotype: therapeutic implications for pulmonary hypertension (2015 Grover Conference series).
abstract: Pulmonary hypertension (PH) is a complex and multifactorial disease involving genetic, epigenetic, and environmental factors. Numerous stimuli and pathological conditions facilitate severe vascular remodeling in PH by activation of a complex cascade of signaling pathways involving vascular cell proliferation, differentiation, and inflammation. Multiple signaling cascades modulate the activity of certain sequence-specific DNA-binding transcription factors (TFs) and coregulators that are critical for the transcriptional regulation of gene expression that facilitates PH-associated vascular cell phenotypes, as demonstrated by several studies summarized in this review. Past studies have largely focused on the role of the genetic component in the development of PH, while the presence of epigenetic alterations such as microRNAs, DNA methylation, histone levels, and histone deacetylases in PH is now also receiving increasing attention. Epigenetic regulation of chromatin structure is also recognized to influence gene expression in development or disease states. Therefore, a complete understanding of the mechanisms involved in altered gene expression in diseased cells is vital for the design of novel therapeutic strategies. Recent technological advances in DNA sequencing will provide a comprehensive improvement in our understanding of mechanisms involved in the development of PH. This review summarizes current concepts in TF and epigenetic control of cell phenotype in pulmonary vascular disease and discusses the current issues and possibilities in employing potential epigenetic or TF-based therapies for achieving complete reversal of PH.
authors.affiliation: Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, member of the German Center for Lung Research (DZL), Bad Nauheim, Germany; Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), member of the DZL, Justus-Liebig University, Giessen, Germany.
authors.forename: Soni S
authors.initials: SS
authors.lastname: Pullamsetti
authors.affiliation: Université Paris-Sud; and Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche (UMR_S) 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Perros
authors.affiliation: Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, member of the German Center for Lung Research (DZL), Bad Nauheim, Germany.
authors.forename: Prakash
authors.initials: P
authors.lastname: Chelladurai
authors.affiliation: University of Arizona, Tucson, Arizona, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Cardiovascular Pulmonary Research Laboratories, Department of Medicine and Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Stenmark
keywords: epigenetics; epigenetics/transcription factor–based therapies; histone deacetylases; pulmonary arterial hypertension; transcription factors