A cryptic tudor domain links BRWD2/PHIP to COMPASS-mediated histone H3K4 methylation

Marc A.J. Morgan, Ryan A. Rickels, Clayton K. Collings, Xiaolin He, Kaixiang Cao, Hans Martin Herz, Kira A. Cozzolino, Nebiyu A. Abshiru, Stacy A. Marshall, Emily J. Rendleman, Christie C. Sze, Andrea Piunti, Neil L. Kelleher, Jeffrey N. Savas, Ali Shilatifard*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Histone H3 Lys4 (H3K4) methylation is a chromatin feature enriched at gene cis-regulatory sequences such as promoters and enhancers. Here we identify an evolutionarily conserved factor, BRWD2/PHIP, which colocalizes with histone H3K4 methylation genome-wide in human cells, mouse embryonic stem cells, and Drosophila. Biochemical analysis of BRWD2 demonstrated an association with the Cullin-4-RING ubiquitin E3 ligase-4 (CRL4) complex, nucleosomes, and chromatin remodelers. BRWD2/PHIP binds directly to H3K4 methylation through a previously unidentified chromatin-binding module related to Royal Family Tudor domains, which we named the CryptoTudor domain. Using CRISPR-Cas9 genetic knockouts, we demonstrate that COMPASS H3K4 methyltransferase family members differentially regulate BRWD2/PHIP chromatin occupancy. Finally, we demonstrate that depletion of the single Drosophila homolog dBRWD3 results in altered gene expression and aberrant patterns of histone H3 Lys27 acetylation at enhancers and promoters, suggesting a cross-talk between these chromatin modifications and transcription through the BRWD protein family.

Original languageEnglish (US)
Pages (from-to)2003-2014
Number of pages12
JournalGenes and Development
Volume31
Issue number19
DOIs
StatePublished - Oct 1 2017

Keywords

  • BRWD
  • COMPASS
  • H3K4
  • Histone methylation
  • PHIP
  • Tudor domain

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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