Drosophila STAT Is Required for Directly Maintaining HP1 Localization and Heterochromatin Stability

Nat Cell Biol. 2008 Apr;10(4):489-96. doi: 10.1038/ncb1713. Epub 2008 Mar 16.

Abstract

STAT (Signal transducer and activator of transcription) is a potent transcription factor and its aberrant activation by phosphorylation is associated with human cancers. We have shown previously that overactivation of JAK, which phosphorylates STAT, disrupts heterochromatin formation globally in Drosophila melanogaster. However, it remains unclear how this effect is mediated and whether STAT is involved. Here, we demonstrate that Drosophila STAT (STAT92E) is involved in controlling heterochromatin protein 1 (HP1) distribution and heterochromatin stability. We found, unexpectedly, that loss of STAT92E, had the same effects as overactivation of JAK in disrupting heterochromatin formation and heterochromatic gene silencing, whereas overexpression of STAT92E had the opposite effects. We have further shown that the unphosphorylated or 'transcriptionally inactive' form of STAT92E is localized on heterochromatin in association with HP1, and is required for stabilizing HP1 localization and histone H3 Lys 9 methylation (H3mK9) . However, activation by phosphorylation reduces heterochromatin-associated STAT92E, causing HP1 displacement and heterochromatin destabilization. Thus, reducing levels of unphosphorylated STAT92E, either by loss of STAT92E or increased phosphorylation, causes heterochromatin instability. These results suggest that activation of STAT by phosphorylation controls both access to chromatin and activity of the transcription machinery.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromosomal Instability*
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Cycloheximide / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / anatomy & histology
  • Drosophila melanogaster / embryology
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / metabolism
  • Embryo, Nonmammalian / anatomy & histology
  • Embryo, Nonmammalian / metabolism
  • Gene Silencing
  • Heterochromatin / metabolism*
  • Humans
  • Janus Kinase 1 / genetics
  • Janus Kinase 1 / metabolism
  • Lysine / metabolism
  • Protein Synthesis Inhibitors / metabolism
  • RNA Interference
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • STAT Transcription Factors / genetics
  • STAT Transcription Factors / metabolism*

Substances

  • Chromosomal Proteins, Non-Histone
  • Drosophila Proteins
  • Heterochromatin
  • Protein Synthesis Inhibitors
  • Recombinant Fusion Proteins
  • STAT Transcription Factors
  • Stat92E protein, Drosophila
  • heterochromatin-specific nonhistone chromosomal protein HP-1
  • Cycloheximide
  • Janus Kinase 1
  • Lysine