FOSL2 binding to enhancer elements regulates endothelial cell state in systemic sclerosis pulmonary vascular disease

Systemic Sclerosis (SSc) is characterized by fibrosis and vasculopathy affecting the skin and internal organs, leading to multi-organ dysfunction. Injury of microvascular ECs in SSc impairs blood flow and causes tissue ischemia, leading to vascular complications such as Raynaud’s, digital ulcers, and pulmonary hypertension (PH). PH in SSc presents as group 1 pulmonary arterial hypertension (PAH) or as group 3 PH related to hypoxia and interstitial lung disease (ILD), both major causes of mortality. Analysis of multiome data from SSc ILD-PH lungs inferred transcription factors regulating EC phenotype, including FOSL2. Overexpression of FOSL2 in transgenic mice (Fosl2tg) leads to vascular changes mirroring human SSc-PH, such as intimal thickening and fibrosis. ScRNA-seq analysis of altered EC gene expression in the Fosl2tg mice showed strong overlap with altered EC gene in SSc-ILD-PH. Overlapping as well as discrete EC gene expression in SuGene/hxpoxia- and hypoxia-treated mice suggested that FOSL2 regulates both hypoxia-dependent and independent pathways in Fosl2tg mice and SSc-ILD-PH. The deep learning model, ChromBPNet, inferred increased AP-1 binding at base pair resolution in SSc-ILDPH ECs and binding to the same motifs was found upon FOSL2 overexpression in primary vascular ECs, highlighting FOSL2’s key role in driving the pathological changes seen in SSc-ILDPH.