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Mediator 1 Regulation of the BMP/TGF-b Signaling in Endothelium: Implications for Pulmonary Hypertension

ABSTRACT: We investigate the MED1/KLF4 co-regulation of the BMP/TGF-beta axes in endothelium by studying the epigenetic regulation of BMP receptor type II (BMPR2), ETS-related gene (ERG), and TGF-beta receptor 2 (TGFBR2) and their involvement in the PH. High throughput screening involving data from RNA-seq, MED1 ChIP-seq, H3K27ac ChIP-seq, KLF4 ATAC-seq, and high-throughput chromosome conformation capture (HiC) together with in silico computations were used to explore the epigenetic and transcriptional regulation of BMPR2, ERG, and TGFBR2 by MED1 and KLF4. In vitro experiments with cultured pulmonary arterial endothelial cells (PAECs) and bulk assays were used to validate results from these in silico analyses. Lung tissue from patients with idiopathic pulmonary arterial hypertension (IPAH), animals with experimental PH, and mice with endothelial ablation of MED1 (EC-MED1-/-) were used to study the PH-protective effect of MED1. Levels of MED1 were decreased in lung tissue or PAECs from IPAH patients and rodent PH models. Mechanistically, MED1 acted synergistically with KLF4 to transactivate BMPR2, ERG, and TGFBR2 via chromatin remodeling and enhancer-promoter interactions. EC-MED1-/- mice showed PH susceptibility. In contrast, MED1 overexpression mitigated the PH phenotype in rodents. A homeostatic regulation of BMPR2, ERG, and TGFBR2 in ECs by MED1 synergistic with KLF4 is essential for the normal function of the pulmonary endothelium. Dysregulation of MED1 and the resulting impairment of the BMP/TGF- signaling is implicated in the disease progression of PAH in humans and PH in rodent models.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212816 | GEO | 2022/09/27

REPOSITORIES: GEO

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Project description:Bmpr2 mutations are critical risk factors for hereditary pulmonary arterial hypertension (hPAH) with approximately 20% of carriers developing disease. There is an unmet medical need to understand how environmental factors, such as inflammation, render Bmpr2 mutants susceptible to PAH. Overexpressing 5-lipoxygenase (5-LO) provokes lung inflammation and transient PAH in Bmpr2+/- mice. Accordingly, 5-LO and its metabolite, leukotriene B4 (LTB4), are candidates for the ‘second hit’. The purpose of this study was to determine how 5-LO-mediated pulmonary inflammation synergized with phenotypically-silent Bmpr2 defects to elicit significant pulmonary vascular disease in rats. Monoallelic Bmpr2 mutant rats were generated and found phenotypically normal for up to one year of observation. To evaluate whether a second hit would elicit disease, animals were exposed to 5-LO-expressing adenovirus (AdAlox5), monocrotaline, SU5416 or chronic hypoxia and analyzed. Bmpr2-mutant hPAH patient samples were assessed for neointimal 5-LO expression. Pulmonary artery endothelial cells (PAECs) were cultured with lentivirus expressing short hairpin RNA (shRNA) targeting Bmpr2 (shBmpr2) to model the impaired BMPR2 signaling, and were then exposed to 5-LO-expressing adenovirus (AdAlox5), and were assessed for phenotypic and transcriptomic changes. In vitro, BMPR2 deficiency, compounded by 5-LO-mediated inflammation, generated apoptosis-resistant and proliferative PAECs with mesenchymal characteristics. These transformed cells expressed nuclear envelop-localized 5-LO consistent with induced LTB4 production, as well as a transcriptomic signature similar to clinical disease, including upregulated NF-kB, IL-6 and TGF-β signaling pathways. The reversal of PAH and vasculopathy in Bmpr2 mutants by TGF-β antagonism suggests that TGF-β is critical for neointimal transformation. Thus, in a new two-hit model of disease, lung inflammation induced severe PAH pathology in Bmpr2+/- rats. Endothelial transformation required the activation of canonical and noncanonical TGF-β signaling pathways and was characterized by 5-LO nuclear envelope translocation with enhanced LTB4 production. This study offers one explanation of how an environmental injury unleashes the destructive potential of an otherwise-silent genetic mutation.

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Mediator 1 Regulation of the BMP/TGF-b Signaling in Endothelium: Implications for Pulmonary Hypertension

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