A trivalent nucleosome interaction by PHIP/BRWD2 is disrupted in neurodevelopmental disorders and cancer

Marc A.J. Morgan*, Irina K. Popova, Anup Vaidya, Jonathan M. Burg, Matthew R. Marunde, Emily J. Rendleman, Zachary J. Dumar, Rachel Watson, Matthew J. Meiners, Sarah A. Howard, Natalia Khalatyan, Robert M. Vaughan, Scott B. Rothbart, Michael C. Keogh, Ali Shilatifard

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in the PHIP/BRWD2 chromatin regulator cause the human neurodevelopmental disorder Chung-Jansen syndrome, while alterations in PHIP expression are linked to cancer. Precisely how PHIP functions in these contexts is not fully understood. Here we demonstrate that PHIP is a chromatin-associated CRL4 ubiquitin ligase substrate receptor and is required for CRL4 recruitment to chromatin. PHIP binds to chromatin through a trivalent reader domain consisting of a H3K4-methyl binding Tudor domain and two bromodomains (BD1 and BD2). Using semisynthetic nucleosomes with defined histone post-translational modifications, we characterize PHIPs BD1 and BD2 as respective readers of H3K14ac and H4K12ac, and identify human disease-associated mutations in each domain and the intervening linker region that likely disrupt chromatin binding. These findings provide new insight into the biological function of this enigmatic chromatin protein and set the stage for the identification of both upstream chromatin modifiers and downstream targets of PHIP in human disease.

Original languageEnglish (US)
Pages (from-to)1642-1656
Number of pages15
JournalGenes and Development
Volume35
Issue number23-24
DOIs
StatePublished - Dec 1 2021

Keywords

  • Chromatin
  • Histone
  • Neurodevelopmental disorder
  • Neuroepigenetics

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Fingerprint

Dive into the research topics of 'A trivalent nucleosome interaction by PHIP/BRWD2 is disrupted in neurodevelopmental disorders and cancer'. Together they form a unique fingerprint.

Cite this