Loss of SETDB1 decompacts the inactive X chromosome in part through reactivation of an enhancer in the IL1RAPL1 gene

Epigenetics Chromatin. 2018 Aug 13;11(1):45. doi: 10.1186/s13072-018-0218-9.


Background: The product of dosage compensation in female mammals is the inactive X chromosome (Xi). Xi facultative heterochromatin is organized into two different types, one of which is defined by histone H3 trimethylated at lysine 9 (H3K9me3). The rationale for this study was to assess SET domain bifurcated 1 (SETDB1) as a candidate for maintaining this repressive modification at the human Xi.

Results: Here, we show that loss of SETDB1 does not result in large-scale H3K9me3 changes at the Xi, but unexpectedly we observed striking decompaction of the Xi territory. Close examination revealed a 0.5 Mb region of the Xi that transitioned from H3K9me3 heterochromatin to euchromatin within the 3' end of the IL1RAPL1 gene that is part of a common chromosome fragile site that is frequently deleted or rearranged in patients afflicted with intellectual disability and other neurological ailments. Centrally located within this interval is a powerful enhancer adjacent to an ERVL-MaLR element. In the absence of SETDB1, the enhancer is reactivated on the Xi coupled with bidirectional transcription from the ERVL-MaLR element. Xa deletion of the enhancer/ERVL-MaLR resulted in loss of full-length IL1RAPL1 transcript in cis, coupled with trans decompaction of the Xi chromosome territory, whereas Xi deletion increased detection of full-length IL1RAPL1 transcript in trans, but did not impact Xi compaction.

Conclusions: These data support a critical role for SETDB1 in maintaining the ERVL-MaLR element and adjacent enhancer in the 3' end of the IL1RAPL1 gene in a silent state to facilitate Xi compaction.

Keywords: Enhancer; Euchromatin; Heterochromatin; IL1RAPL1; Inactive X chromosome; SETDB1; X chromosome inactivation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Chromatin Assembly and Disassembly
  • Enhancer Elements, Genetic
  • Female
  • HEK293 Cells
  • Histone Code
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Interleukin-1 Receptor Accessory Protein / genetics*
  • Interleukin-1 Receptor Accessory Protein / metabolism
  • Protein Methyltransferases / genetics*
  • X Chromosome Inactivation*


  • IL1RAPL1 protein, human
  • Interleukin-1 Receptor Accessory Protein
  • Protein Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • SETDB1 protein, human