Synergy of Eed and Tsix in the repression of Xist gene and X-chromosome inactivation.
X-chromosome inactivation (XCI) depends on the noncoding Xist gene. Xist transcription is negatively regulated by its antisense partner Tsix, whose disruption results in nonrandom XCI in females. However, males can maintain Xist in a repressed state without Tsix, indicating participation of additional factor(s) in the protection of the single male X from inactivation. Here, we provide evidence that the histone methyltransferase Eed is also involved in the process. Male embryonic stem cells with Eed-null and Tsix mutations (X(Delta)Y Eed-/-) showed Xist hyperactivation upon differentiation, whereas cells with either mutation alone did not. Impaired X-linked gene expression was observed in the X(Delta)Y Eed-/- ES cells at the onset of differentiation. The Xist promoter in the X(Delta)Y Eed-/- cells showed elevated histone H3-dimethyl lysine 4 modifications and lowered CpG methylation, which are characteristics of open chromatin. Hence, we identified Eed as an additional major player in the regulation of Xist expression. The synergy of Polycomb group proteins and antisense Tsix transcription in Xist gene regulation explains why males can repress Xist without Tsix.
Department of Stem Cell Biology, Graduate School of Medicine, Kanazawa University, Takara-machi, Kanazawa, Ishikawa, Japan. shinwa@med.kanazawa-u.ac.jp
Shinwa
S
Shibata
Takashi
T
Yokota
Anton
A
Wutz
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D018899:CpG Islands; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D005260:Female; D006657:Histones / Q000378:metabolism; D008297:Male; D051379:Mice; D063151:Polycomb Repressive Complex 2; D011401:Promoter Regions, Genetic; D016372:RNA, Antisense / Q000378:metabolism; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014960:X Chromosome / Q000378:metabolism*; D049951:X Chromosome Inactivation
C107275:Eed protein, mouse; D006657:Histones; D016372:RNA, Antisense; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D012097:Repressor Proteins; C465658:Tsix transcript, mouse; C077885:XIST non-coding RNA; D063151:Polycomb Repressive Complex 2