Variability of cross-tissue X-chromosome inactivation characterizes timing of human embryonic lineage specification events

• DOI: 10.1016/j.devcel.2022.07.007
• Publication Date: 2022-07-31T10:56:51Z
• Authors: Jonathan M. Werner; Sara Ballouz; John Hover; Jesse Gillis
• Keywords: Adult; 570; 1.1 Normal biological development and functioning; embryonic stochasticity; allele-specific expression; 3105 Genetics; Chromosomes; developmental lineage; 03 medical and health sciences; X Chromosome Inactivation; Genetics; Animals; Humans; anzsrc-for: 31 Biological Sciences; Mammals; X; Chromosomes, Human, X; 0303 health sciences; Mammalian; X-chromosome inactivation; 500; anzsrc-for: 3101 Biochemistry and cell biology; Embryo, Mammalian; anzsrc-for: 3105 Genetics; human development; anzsrc-for: 11 Medical and Health Sciences; Embryo; escape from XCI; anzsrc-for: 06 Biological Sciences; Generic health relevance; 31 Biological Sciences; Human

X-chromosome inactivation (XCI) is a random, permanent, and developmentally early epigenetic event that occurs during mammalian embryogenesis. We harness these features to investigate characteristics of early lineage specification events during human development. We initially assess the consistency of X-inactivation and establish a robust set of XCI-escape genes. By analyzing variance in XCI ratios across tissues and individuals, we find that XCI is shared across all tissues, suggesting that XCI is completed in the epiblast (in at least 6-16 cells) prior to specification of the germ layers. Additionally, we exploit tissue-specific variability to characterize the number of cells present during tissue-lineage commitment, ranging from approximately 20 cells in liver and whole blood tissues to 80 cells in brain tissues. By investigating the variability of XCI ratios using adult tissue, we characterize embryonic features of human XCI and lineage specification that are otherwise difficult to ascertain experimentally.