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

IF 11.1 Q1 CELL BIOLOGY Cell genomics Pub Date : 2024-08-14 Epub Date: 2024-07-30 DOI:10.1016/j.xgen.2024.100625
Yoshihiko Tomofuji, Ryuya Edahiro, Kyuto Sonehara, Yuya Shirai, Kian Hong Kock, Qingbo S Wang, Shinichi Namba, Jonathan Moody, Yoshinari Ando, Akari Suzuki, Tomohiro Yata, Kotaro Ogawa, Tatsuhiko Naito, Ho Namkoong, Quy Xiao Xuan Lin, Eliora Violain Buyamin, Le Min Tan, Radhika Sonthalia, Kyung Yeon Han, Hiromu Tanaka, Ho Lee, Tatsusada Okuno, Boxiang Liu, Koichi Matsuda, Koichi Fukunaga, Hideki Mochizuki, Woong-Yang Park, Kazuhiko Yamamoto, Chung-Chau Hon, Jay W Shin, Shyam Prabhakar, Atsushi Kumanogoh, Yukinori Okada
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Abstract

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.

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利用单细胞全息数据对 X 染色体失活逃逸进行量化,揭示了不同细胞类型和组织之间的异质性。
有几个 X 连锁基因从 X 染色体失活(XCI)中逃逸出来,而不同细胞类型和组织中逃逸基因的差异还没有得到很好的描述。在这里,我们开发了 scLinaX,利用基于液滴的单细胞 RNA 测序(scRNA-seq)数据直接量化来自失活 X 染色体的相对基因表达。利用 scLinaX 和大规模血液 scRNA-seq 数据集进行的差异表达基因分析一致发现,淋巴细胞中的逸漏比髓系细胞中的逸漏更强。将 scLinaX 扩展到 10 倍多组数据集(scLinaX-multi)表明,在染色质可及性水平上,淋巴细胞比髓系细胞有更强的逃避能力。对人类多器官 scRNA-seq 数据集进行的 scLinaX 分析也发现,淋巴组织和淋巴细胞对 XCI 的逃避程度相对较强。最后,性别间全基因组关联研究的效应大小比较表明,逸出对基因型-表型关联有潜在影响。总之,scLinaX 和量化的逃逸目录确定了不同细胞类型和组织中逃逸的异质性。
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