Super-Enhancer Target Gene CBP/p300-Interacting Transactivator With Glu/Asp-Rich C-Terminal Domain, 2 Cooperates With Transcription Factor Forkhead Box J3 to Inhibit Pulmonary Vascular Remodeling

Area of Science:

• Molecular Biology
• Genetics
• Cardiovascular Research

Background:

• Pulmonary hypertension (PH) involves pulmonary artery smooth muscle cell (PASMC) proliferation, but the role of super-enhancers (SEs) is unclear.
• Identifying key genes regulated by SEs is crucial for understanding PH pathogenesis.

Purpose of the Study:

• To investigate the function of SEs in PH, specifically their role in PASMC proliferation.
• To identify and characterize SEs-targeted genes involved in PH.

Main Methods:

• Chromatin immunoprecipitation (ChIP)-sequencing using H3K27ac antibody to identify SEs-targeted genes in PASMCs.
• Bioinformatics prediction, ChIP-PCR, and dual-luciferase reporter assays to validate CITED2 as an SEs-targeted gene.
• Analysis of CITED2 and FOXJ3 expression in hypoxic mouse PASMCs, iPAH patients, and hypoxia-exposed human PASMCs.

Main Results:

• CBP/p300-interacting transactivator with Glu/Asp-rich C-terminal domain, 2 (CITED2) was identified as an SEs-targeted gene.
• Expression of CITED2 and Forkhead Box J3 (FOXJ3) was reduced in hypoxic PASMCs and in patients with idiopathic pulmonary arterial hypertension (iPAH).
• Overexpression of CITED2 attenuated hypoxia-induced PASMC proliferation and reversed a hypoxia-induced PH mouse model, mediated by FOXJ3 binding to SEs.

Conclusions:

• CITED2 is an SEs-targeted gene regulated by FOXJ3.
• The FOXJ3/SEs/CITED2 axis represents a novel therapeutic target for pulmonary hypertension.