Abstract
Long non-coding RNA Xist plays a crucial role in establishing and maintaining X-chromosome inactivation (XCI) which is a paradigm of long non-coding RNA-mediated gene regulation. Xist has Xist-specific repeat elements A-F which are conserved among eutherian mammals, underscoring their functional importance. Here we report that Xist RNA repeat E, a conserved Xist repeat element in the Xist exon 7, interacts with ASH2L and contributes to maintenance of escape gene expression level on the inactive X-chromosome (Xi) during XCI. The Xist repeat E-deletion mutant female ES cells show the depletion of ASH2L from the Xi upon differentiation. Furthermore, a subset of escape genes exhibits unexpectedly higher expression in the repeat E mutant cells than the cells expressing wildtype Xist during X-inactivation, whereas the silencing of X-linked non-escape genes is not affected. We discuss the implications of these results to understand the role of ASH2L and Xist repeat E for histone modifications and escape gene regulation during random X-chromosome inactivation.
Highlights
To equalize the imbalance of X-linked gene dosage between genders, one of the two X chromosomes in female mammals is converted to the transcriptionally inactive X-chromosome (Xi) at the early phase of development whereby the majority of X-linked genes on the Xi are silenced [1,2,3]
Xist long noncoding RNA induces X chromosome inactivation by recruiting multiple chromatin modifying enzymes to the inactive X-chromosome. Among such chromatin modifying enzymes, ASH2L is unique since it is a component of the MLL/SET complexes, which are a histone lysine 4 methyltransferase for transcriptional activation
Among the novel results in our paper, we found that ASH2L binds to the repeat E of Xist RNA
Summary
To equalize the imbalance of X-linked gene dosage between genders, one of the two X chromosomes in female mammals is converted to the transcriptionally inactive X-chromosome (Xi) at the early phase of development whereby the majority of X-linked genes on the Xi are silenced [1,2,3]. In mice, imprinted X-chromosome inactivation (XCI) starts from as early as 2-4-cell stage in which the paternal X-chromosome is always silenced, and the paternally imprinted Xi is sustained in the cells of the trophectoderm and primitive endoderm, which give rise to the extra-embryonic tissues [4,5]. Once random XCI is established in epiblast lineage, the Xi is inherited throughout successive cell divisions to continue balancing X-linked gene dosage between males and females. Several models have been proposed to explain how escape genes evade XCI under the chromosome-wide heterochromatic environment on the Xi [6,8], the underlying mechanism for escaping XCI remains unknown
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