Inactive X chromosome-specific histone H3 modifications and CpG hypomethylation flank a chromatin boundary between an X-inactivated and an escape gene.
In mammals, the dosage compensation of sex chromosomes between males and females is achieved by transcriptional inactivation of one of the two X chromosomes in females. However, a number of genes escape X-inactivation in humans. It remains poorly understood how the transcriptional activity of these 'escape genes' is maintained despite the chromosome-wide heterochromatin formation. To address this question, we analyzed a putative chromatin boundary between the inactivated RBM10 and an escape gene, UBA1/UBE1. Chromatin immunoprecipitation revealed that trimethylated histone H3 lysine 9 and H4 lysine 20 were enriched in the last exon through the proximal downstream region of RBM10, but were remarkably diminished at approximately 2 kb upstream of the UBA1 transcription start site. Whereas RNA polymerase II was not loaded onto the intergenic region, CTCF (CCCTC binding factor) was enriched around the boundary, where some CpG sites were hypomethylated specifically on inactive X. These findings suggest that local DNA hypomethylation and CTCF binding are involved in the formation of a chromatin boundary, which protects the UBA1 escape gene against the chromosome-wide transcriptional silencing.
Goto
Yuji
Y
Nuclear Function and Dynamics Unit, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Kimura
Hiroshi
H
D000076246:CCCTC-Binding Factor; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D021901:DNA, Intergenic / Q000737:chemistry; D004171:Diploidy; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006822:Hybrid Cells; D016601:RNA-Binding Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics*; D049951:X Chromosome Inactivation
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002843:Chromatin; D021901:DNA, Intergenic; D006657:Histones; C512260:RBM10 protein, human; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C471538:UBA1 protein, human; D044764:Ubiquitin-Activating Enzymes