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

Mol Cell Biol. 2021 Jul 23;41(8):e0038220. doi: 10.1128/MCB.00382-20. Epub 2021 Jul 23.


The long noncoding 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.

Keywords: CTCF; XIST; YY1; cis regulatory element; pluripotency factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CCCTC-Binding Factor / genetics
  • CCCTC-Binding Factor / metabolism*
  • Embryonic Stem Cells / metabolism*
  • Humans
  • RNA, Long Noncoding / genetics*
  • Regulatory Sequences, Nucleic Acid / genetics
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • X Chromosome Inactivation / genetics
  • X Chromosome Inactivation / physiology*


  • CCCTC-Binding Factor
  • CTCF protein, human
  • RNA, Long Noncoding
  • Repressor Proteins
  • XIST non-coding RNA