XCI and sex-biased expression in AT2 cells
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ABSTRACT: Significant sex differences exist for many lung pathologies, including SARS-CoV-2 related disease (COVID-19) and pulmonary fibrosis, but the mechanistic basis for this remains unclear. Notably, Ace2, the gene encoding angiotensin-converting enzyme 2, an enzyme that plays multiple roles in SARS-CoV-2 pathogenesis, including acting as the major viral receptor, is localized on the X-chromosome. Moreover, prior work in fibroblasts suggested that Ace2 may escape X-Chromosome Inactivation (XCI), which normalizes X-lined gene expression between sexes. Alveolar type 2 cells (AT2s), which play a key role in alveolar lung regeneration, express Ace2, suggesting that aberrant XCI in AT2s could potentially impact sex-biased lung pathology. To that end, we performed RNA-seq on AT2 cells isolated from 4 male and 4 female F1 mus/cast mice. Utilizing allele-specific transcriptomics, we demonstrate that about 50% of expressed X-linked genes in mouse AT2s, including Ace2, escape XCI, the highest levels reported to date. Moreover, we observe dramatic genome-wide expression differences between male and female AT2s, likely influencing both lung physiology and pathophysiologic responses. Taken together, these studies support a renewed focus on AT2s as potential contributor to sex-biased differences in lung disease.
ORGANISM(S): Mus musculus
PROVIDER: GSE203166 | GEO | 2023/01/16
REPOSITORIES: GEO
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