Unusual X chromosome inactivation maintenance in female alveolar type 2 cells is correlated with increased numbers of X-linked escape genes and sex-biased gene expression

• Published in: Stem cell reports 2023-02, Vol.18 (2), p.489-502
• Main Authors: Sierra, Isabel, Pyfrom, Sarah, Weiner, Aaron, Zhao, Gan, Driscoll, Amanda, Yu, Xiang, Gregory, Brian D., Vaughan, Andrew E., Anguera, Montserrat C.
• Format: Article
• Language: English
• Subjects: Ace2; alveolar type 2 cells; Angiotensin-Converting Enzyme 2 - genetics; Angiotensin-Converting Enzyme 2 - metabolism; Animals; COVID-19 - genetics; Female; Genes, X-Linked; heterochromatic modifications; Humans; lung progenitors; Male; Mice; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; SARS-CoV-2 - genetics; sex differences; sex-biased gene expression; Transcriptome; X chromosome inactivation; X Chromosome Inactivation - genetics; XCI escape genes; Xist RNA
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2022.12.005

Sex differences exist for many lung pathologies, including COVID-19 and pulmonary fibrosis, but the mechanistic basis for this remains unclear. Alveolar type 2 cells (AT2s), which play a key role in alveolar lung regeneration, express the X-linked Ace2 gene that has roles in lung repair and SARS-CoV-2 pathogenesis, suggesting that X chromosome inactivation (XCI) in AT2s might impact sex-biased lung pathology. Here we investigate XCI maintenance and sex-specific gene expression profiles using male and female AT2s. Remarkably, the inactive X chromosome (Xi) lacks robust canonical Xist RNA “clouds” and less enrichment of heterochromatic modifications in human and mouse AT2s. We demonstrate that about 68% of expressed X-linked genes in mouse AT2s, including Ace2, escape XCI. There are genome-wide expression differences between male and female AT2s, likely influencing both lung physiology and pathophysiologic responses. These studies support a renewed focus on AT2s as a potential contributor to sex-biased differences in lung disease. •XCI maintenance and sex-specific gene expression profiles of alveolar type 2 cells•The Xi lacks Xist RNA “clouds” and less heterochromatic mark enrichment•68% of expressed X-linked genes in mouse AT2s, including Ace2, escape XCI•Genome-wide sex-specific gene expression profile differences in AT2s Anguera, Vaughan, and colleagues show that lung alveolar type 2 (AT2s) cells maintain X chromosome inactivation with fewer epigenetic modifications on the inactive X, with very high numbers of X-linked genes that “escape” transcriptional silencing. AT2 cells also exhibit significant genome-wide sex-biased gene expression, which likely influences lung physiology and pathophysiologic responses.