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Open Access

DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1‐mediated transcriptional repression

Suk Min Jang, Saliha Azebi, Guillaume Soubigou, Christian Muchardt

Author Affiliations

  1. Suk Min Jang1,2,3,
  2. Saliha Azebi1,2,3,
  3. Guillaume Soubigou4 and
  4. Christian Muchardt*,1,2
  1. 1Institut Pasteur, Dpt Biologie du Développement et Cellules Souches Unité de Régulation Epigénétique, Paris, France
  2. 2URA2578, CNRS, Paris, France
  3. 3Sorbonne Universités UPMC Univ Paris06, IFD, Paris cedex05, France
  4. 4Institut Pasteur, Dpt Génomes et Génétique, Plate‐forme Transcriptome et Epigénome, Paris, France
  1. *Corresponding author. Tel.: +33 145688525; E‐mail: christian.muchardt{at}pasteur.fr

Abstract

Heterochromatin protein 1 (HP1) proteins are chromatin‐bound transcriptional regulators. While their chromodomain binds histone H3 methylated on lysine 9, their chromoshadow domain associates with the H3 histone fold in a region involved in chromatin remodeling. Here, we show that phosphorylation at histone H3 threonine 45 and serine 57 within this latter region differentially affects binding of the three mammalian HP1 isoforms HP1α, HP1β and HP1γ. Both phosphorylation events are dependent on the activity of the DYRK1A kinase that antagonizes HP1‐mediated transcriptional repression and participates in abnormal activation of cytokine genes in Down's syndrome‐associated megakaryoblastic leukemia.

Synopsis

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DYRK1A counteracts chromatin‐mediated transcriptional repression of pro‐inflammatory genes by phosphorylating histone H3 at the genes' promoters. Inhibiting excessive DYRK1A activity in megakaryoblastic leukemia linked to Down's syndrome might be a way to control the pro‐inflammatory cytokinemia associated with this disease.

  • Binding of HP1α, HP1β, and HP1γ to the globular domain of histone H3 is differentially regulated by phosphorylation of residues H3T45 and H3S57.

  • At pro‐inflammatory gene promoters, the Down's syndrome‐associated DYRK1A kinase phosphorylates these histone H3 residues and interferes with HP1‐mediated transcriptional repression.

  • Inhibition of DYRK1A activity in megakaryoblastic leukemia cells from Down's syndrome patients decreases the expression of pro‐inflammatory genes.

  • Received December 12, 2013.
  • Revision received March 24, 2014.
  • Accepted March 26, 2014.

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