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

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 HP1a, HP1b and HP1c. 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 Downs syndrome-associated megakaryoblastic leukemia.

Histone Core Phosphorylation Regulates DNA Accessibility

“…Together, these results indicate that histone PTMs within the DNA entry-exit region of the nucleosome generally increase DNA accessibility by about 3-fold. These PTMs are involved in transcription activation (21,22,31,33,35,37), and H3Y41ph (34) and H3K56ac (19,20) have both been identified by ChIP sequencing to occur within nucleosomes in the regions around the transcription start site. Therefore, this unwrapping mechanism is consistent with a biological function where these PTMs increase DNA accessibility to transcription regulatory complexes facilitating gene expression.…”

“…Because both H3K56ac and H3Y41ph influence transcription, these modifications could occur within the same nucleosome. H3T45 is phosphorylated in human cells by PKC␦ (32) and DYRK1A (35). PKC␦ phosphorylation is associated with apoptosis, whereas DYRK1A phosphorylation represses HP1 binding similarly to H3Y41ph.…”

Insights into newly discovered marks and readers of epigenetic information

“…26,27). Dimethylation of H3R42 (H3R42me2) stimulates gene expression from chromatinized templates, probably through a disruption of DNA rewrapping onto the nucleosome core 28 , and H3T45ph or H3S57ph precludes HP1-mediated repression of a set of stress-response genes 29 .…”

Beyond the histone tale: HP1α deregulation in breast cancer epigenetics

“…SWI/ SNF ATPase activity facilitates the HP1 binding for functional detection and arrest of chromatin remodeling. 48 The H3 histone fold binding of HP1 proteins is disrupted by phosphorylation at H3Y41 by JAK2 kinase and by phosphorylation at H3T45 and H3S57 by DYRK1A kinase where the latter 2 H3 modifications also showed to have influence on the competition of HP1 proteins and BRG1 for binding to the histone fold. These complex networks of H3 histone fold modifications and interactions can thereby affect HP1 chromatin association and HP1 mediated transcriptional repression independent of H3K9 methylation.…”

“…These complex networks of H3 histone fold modifications and interactions can thereby affect HP1 chromatin association and HP1 mediated transcriptional repression independent of H3K9 methylation. 48 When bound to di-or tri-methylated H3K9 through the HP1 CD a subsequent recruitment of SUV39h1 causes adjacent H3K9 residues to become methylated (Fig. 2).…”