Quantification of escape from X chromosome inactivation with single-cell omics data reveals heterogeneity across cell types and tissues

• Published in: Cell genomics Vol. 4; no. 8; p. 100625
• Main Authors: Suzuki, Akari, Naito, Tatsuhiko, Lee, Ho, Majumder, Partha P., Chambers, John C., Rayan, Nirmala Arul, Sankaran, Shvetha, Han, Kyung Yeon, Oh, Jin-Mi, Choi, Murim, Yamamoto, Kenichi, Tachikawa, Natsuo, Kabata, Hiroki, Chubachi, Shotaro, Sasaki, Junichi, Nanki, Kosaku, Nishimura, Tomoyasu, Shibata, Shun, Matsui, Yuma, Nishida, Takashi, Yamamoto, Masaomi, Sasaki, Kana, Ito, Satoshi, Honda, Takayuki, Sonobe, Kazunari, Nakajima, Yukiko, Anan, Ryusuke, Kurihara, Yuko, Nishio, Kazumi, Takei, Reoto, Yamano, Yasuhiko, Saito, Fukuki, Tanaka, Yoshiaki, Uchida, Tomoyuki, Hagiwara, Shigehiro, Nagao, Genta, Murakami, Koji, Yamada, Mitsuhiro, Nakayama, Sohei, Sugihara, Fuminori, Wing, James B., Kawamura, Yusuke, Noda, Yoshimi, Hara, Reina, Kuge, Tomoki, Yamamoto, Yuji, Sasa, Noah, Inohara, Hidenori, Hirata, Haruhiko, Takahashi, Kenichiro, Kamiya, Akane, Kawashima, Hidetoshi, Narita, Atsuya, Niwa, Kazuki, Nishi, Koichi, Mori, Nobuaki, Baba, Tomoya, Yagi, Kazuma, Kuse, Naoyuki, Awano, Nobuyasu, Kozu, Yutaka, Kawamura, Kodai, Omote, Norihito, Ando, Akira, Harada, Masahiro, Shibusawa, Takayuki, Sano, Tomoya, Nakamura, Morio, Fukuyama, Satoru, Kanaoka, Kensuke, Tsuburai, Takahiro, Kanda, Hidenori, Kitagawa, Yuichiro, Fukuta, Tetsuya, Togashi, Yuki, Ishihara, Shoichiro, Kanehiro, Arihiko, Wada, Sae, Umeda, Akira, Ohira, Yoshiyuki, Watanabe, Masafumi, Sagara, Hironori, Ohta, Shin, Minemura, Hiroyuki, Kanai, Masayuki, Imamura, Tomonori, Yatomi, Masakiyo, Tominaga, Yoshiteru, Kashiwada, Takeru, Makino, Shohei, Egi, Moritoki, Kumanogoh, Atsushi, Kimura, Akinori, Kanai, Takanori, Fukunaga, Koichi, Asai, Satoshi, Park, Woong-Yang, Hon, Chung-Chau, Okada, Yukinori
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.08.2024; Elsevier
• Subjects: Animals; Female; Genes, X-Linked - genetics; Genome-Wide Association Study; Humans; Lymphocytes - metabolism; Male; Mice; Myeloid Cells - metabolism; Organ Specificity; Sequence Analysis, RNA - methods; sex differences; Single-Cell Analysis - methods; single-cell omics; X chromosome; X Chromosome Inactivation - genetics; single-cell omics; sex differences; X chromosome
• ISSN: 2666-979X; 2666-979X
• DOI: 10.1016/j.xgen.2024.100625

Several X-linked genes escape from X chromosome inactivation (XCI), while differences in escape across cell types and tissues are still poorly characterized. Here, we developed scLinaX for directly quantifying relative gene expression from the inactivated X chromosome with droplet-based single-cell RNA sequencing (scRNA-seq) data. The scLinaX and differentially expressed gene analyses with large-scale blood scRNA-seq datasets consistently identified the stronger escape in lymphocytes than in myeloid cells. An extension of scLinaX to a 10x multiome dataset (scLinaX-multi) suggested a stronger escape in lymphocytes than in myeloid cells at the chromatin-accessibility level. The scLinaX analysis of human multiple-organ scRNA-seq datasets also identified the relatively strong degree of escape from XCI in lymphoid tissues and lymphocytes. Finally, effect size comparisons of genome-wide association studies between sexes suggested the underlying impact of escape on the genotype-phenotype association. Overall, scLinaX and the quantified escape catalog identified the heterogeneity of escape across cell types and tissues. [Display omitted] •Development of scLinaX software that quantifies escape from XCI with scRNA-seq data•Lymphocytes showed stronger escape from XCI than myeloid cells•Extension of scLinaX to multiome can quantify escape at chromatin-accessibility level•Escape can affect the sex difference of the genotype-phenotype associations Tomofuji et al. developed scLinaX, a software to quantify escape from X chromosome inactivation (XCI). Their analyses identified the heterogeneity of escape across cell types, namely a stronger escape from XCI in lymphocytes than myeloid cells. scLinaX would be a useful tool for understanding the sex differences in gene regulation.