Trans- and cis-acting effects of Firre on epigenetic features of the inactive X chromosome

• Published in: Nature communications Vol. 11; no. 1; pp. 6053 - 17
• Main Authors: Fang, He, Bonora, Giancarlo, Lewandowski, Jordan P., Thakur, Jitendra, Filippova, Galina N., Henikoff, Steven, Shendure, Jay, Duan, Zhijun, Rinn, John L., Deng, Xinxian, Noble, William S., Disteche, Christine M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27-11-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/109; 13/51; 13/89; 14; 14/1; 14/32; 14/63; 45/15; 45/22; 45/23; 45/29; 45/41; 45/43; 45/77; 45/88; 45/90; 45/91; 631/208/176; 631/337/100/101; 631/337/384/2568; 631/337/386; 631/80/386; 64/60; Alleles; Animals; Base Sequence; Cell Line; Cell Nucleus - genetics; Chromatin - metabolism; Chromosome deletion; Chromosomes; DNA, Complementary - genetics; Ectopic expression; Epigenesis, Genetic; Epigenetics; Female; Gene Deletion; Gene expression; Gene Ontology; Genetic Loci; Genome; Histones; Histones - metabolism; Humanities and Social Sciences; Loci; Lymphocytes T; Lysine - metabolism; Male; Methylation; Mice, Inbred C57BL; multidisciplinary; Polycomb group proteins; Polycomb Repressive Complex 2 - metabolism; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Science; Science (multidisciplinary); Somatic cells; Stem cells; Transgenes; Up-Regulation - genetics; X Chromosome - genetics; X Chromosome Inactivation - genetics; X chromosomes
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19879-3

Firre
encodes a lncRNA involved in nuclear organization. Here, we show that
Firre
RNA expressed from the active X chromosome maintains histone H3K27me3 enrichment on the inactive X chromosome (Xi) in somatic cells. This trans-acting effect involves SUZ12, reflecting interactions between
Firre
RNA and components of the Polycomb repressive complexes. Without
Firre
RNA, H3K27me3 decreases on the Xi and the Xi-perinucleolar location is disrupted, possibly due to decreased CTCF binding on the Xi. We also observe widespread gene dysregulation, but not on the Xi. These effects are measurably rescued by ectopic expression of mouse or human
Firre
/
FIRRE
transgenes, supporting conserved trans-acting roles. We also find that the compact 3D structure of the Xi partly depends on the
Firre
locus and its RNA. In common lymphoid progenitors and T-cells
Firre
exerts a cis-acting effect on maintenance of H3K27me3 in a 26 Mb region around the locus, demonstrating cell type-specific trans- and cis-acting roles of this lncRNA.
Firre
encodes a lncRNA involved in nuclear organization in mammals. Here, the authors find that allelic deletion of
Firre
on the active X chromosome (Xa) results in dose-dependent loss of histone H3K27me3 on the inactive X chromosome (Xi), along with other trans-acting effects, including disruption of the perinuclear location and minor dysregulation of gene expression.