Telomere length regulates TERRA levels through increased trimethylation of telomeric H3K9 and HP1α

Nat Struct Mol Biol. 2012 Sep;19(9):948-56. doi: 10.1038/nsmb.2364. Epub 2012 Aug 26.

Abstract

Gene silencing by the repressive telomeric chromatin environment, referred to as telomere position effect (TPE), has been well characterized in yeast and depends on telomere length. However, proof of its existence at native human chromosome ends has remained elusive, mainly owing to the paucity of genes near telomeres. The discovery of TERRAs, the telomeric noncoding RNAs transcribed from subtelomeric promoters, paved the way to probing for telomere-length impact on physiological TPE. Using cell lines of various origins, we show that telomere elongation consistently represses TERRA expression. Repression is mediated by increased trimethylated H3K9 density at telomeres and by heterochromatin protein HP1α, with no detectable spreading of the marks beyond the telomeric tract, restricting human TPE to telomere transcription. Our data further support the existence of a negative-feedback mechanism in which longer TERRA molecules repress their own transcription upon telomere elongation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Line, Tumor
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Down-Regulation
  • Gene Silencing*
  • Histones / metabolism*
  • Humans
  • Methylation
  • Methyltransferases / metabolism
  • RNA, Untranslated / chemistry
  • RNA, Untranslated / genetics*
  • RNA, Untranslated / metabolism
  • Repressor Proteins / metabolism
  • Telomere / chemistry
  • Telomere / genetics
  • Telomere / metabolism*

Substances

  • Chromosomal Proteins, Non-Histone
  • Histones
  • RNA, Untranslated
  • Repressor Proteins
  • heterochromatin-specific nonhistone chromosomal protein HP-1
  • SUV39H1 protein, human
  • Methyltransferases