A Novel cis Regulatory Element Regulates Human XIST in a CTCF-Dependent Manner

Abstract

The long non-coding RNA XIST is the master regulator for the process of X chromosome inactivation (XCI) in mammalian females. Here we report the existence of a hitherto uncharacterized cis regulatory element (cRE) within the first exon of human XIST , which determines the transcriptional status of XIST during the initiation and maintenance phases of XCI. In the initiation phase, pluripotency factors bind to this cRE and keep XIST repressed. In the maintenance phase of XCI, the cRE is enriched for CTCF which activates XIST transcription. By employing a CRISPR-dCas9-KRAB based interference strategy, we demonstrate that binding of CTCF to the newly identified cRE is critical for regulating XIST in a YY1-dependent manner. Collectively, our study uncovers the combinatorial effect of multiple transcriptional regulators influencing XIST expression during the initiation and maintenance phases of XCI.

Escaping but not the inactive X-linked protein complex coding genes may achieve X-chromosome dosage compensation and underlie X chromosome inactivation-related diseases

“…Then we extracted the SP1 binding sites of genes from RegNetwork database [ 30 ] and found that more than 43% (32/73) of EsP genes contain SP1 binding motifs around their promoter regions. SP1 can play parallel roles with YY1 and CTCF in regulating XIST transcription from the XIST promoter [ 31 ]. And the binding motif of SP1 was reported to be exclusively enriched in the regulatory elements on the Xa rather than Xi [ 32 , 33 ].…”