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

• DOI: 10.1016/j.stemcr.2022.12.005
• Publication Date: 2023-01-12T15:34:39Z
• Authors: Isabel Sierra; Sarah Pyfrom; Aaron Weiner; Gan Zhao; Amanda Driscoll; Xiang Yu; Brian D. Gregory; Andrew E. Vaughan; Montserrat C. Ang...
• Keywords: Male; 0303 health sciences; SARS-CoV-2; COVID-19; Article; 3. Good health; Mice; 03 medical and health sciences; X Chromosome Inactivation; Genes, X-Linked; Humans; Animals; Female; RNA, Long Noncoding; Angiotensin-Converting Enzyme 2; Transcriptome

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