MED1 Regulates BMP/TGF-β in Endothelium: Implication for Pulmonary Hypertension

Area of Science:

• Molecular Biology
• Cardiovascular Research
• Epigenetics

Background:

• Dysregulated bone morphogenetic protein (BMP) and transforming growth factor-beta (TGF-β) signaling are critical in pulmonary arterial hypertension (PAH).
• MED1 (mediator complex subunit 1) and KLF4 (Krüppel-like factor 4) are key regulators in endothelium, but their roles in PAH pathogenesis are unclear.
• The epigenetic and transcriptional regulation of BMP/TGF-β axes by MED1/KLF4 in pulmonary endothelium leading to PAH requires investigation.

Purpose of the Study:

• To investigate the co-regulation of BMP/TGF-β signaling pathways by MED1 and KLF4 in the pulmonary endothelium.
• To elucidate the epigenetic regulation of BMPR2, ERG, and TGFBR2 by MED1 and KLF4 in the context of pulmonary hypertension (PH).
• To assess the role of MED1 in the development and progression of PH.

Main Methods:

• Utilized high-throughput screening (RNA-seq, ChIP-seq, ATAC-seq, Hi-C) and in silico analyses to explore epigenetic and transcriptional regulation.
• Validated findings using in vitro cultured pulmonary arterial endothelial cells (ECs) and bulk assays.
• Examined lung tissues from PAH patients, PH animal models, and EC-specific MED1 knockout mice (EC-MED1-/-) to evaluate MED1's protective effects.

Main Results:

• MED1 levels were reduced in lung tissues and ECs from PAH patients and PH models.
• MED1 synergistically activated BMPR2, ERG, and TGFBR2 expression with KLF4 through chromatin remodeling and enhancer-promoter interactions.
• Endothelial MED1 ablation led to PH susceptibility, while MED1 overexpression mitigated PH phenotypes in rodents.

Conclusions:

• Homeostatic regulation of BMPR2, ERG, and TGFBR2 by MED1 and KLF4 in ECs is essential for normal pulmonary endothelium function.
• MED1 dysregulation and subsequent impairment of BMP/TGF-β signaling contribute to PAH progression in humans and PH in rodent models.
• MED1 plays a crucial protective role against the development of pulmonary hypertension.