Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for the epigenetic inheritance of DNA methylation

Scott B. Rothbart; Bradley M. Dickson; Michelle S. Ong; Krzysztof Krajewski; Scott Houliston; Dmitri B. Kireev; Cheryl H. Arrowsmith; Brian D. Strahl

doi:10.1101/gad.220467.113

Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for the epigenetic inheritance of DNA methylation

¹Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
²Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
³Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
⁴Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada;
⁵Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
⁶Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada;
⁷Campbell Family Cancer Research Institute, Toronto, Ontario M5G 2M9, Canada

↵8 These authors contributed equally to this work.

Abstract

Histone post-translational modifications regulate chromatin structure and function largely through interactions with effector proteins that often contain multiple histone-binding domains. While significant progress has been made characterizing individual effector domains, the role of paired domains and how they function in a combinatorial fashion within chromatin are poorly defined. Here we show that the linked tandem Tudor and plant homeodomain (PHD) of UHRF1 (ubiquitin-like PHD and RING finger domain-containing protein 1) operates as a functional unit in cells, providing a defined combinatorial readout of a heterochromatin signature within a single histone H3 tail that is essential for UHRF1-directed epigenetic inheritance of DNA methylation. These findings provide critical support for the “histone code” hypothesis, demonstrating that multivalent histone engagement plays a key role in driving a fundamental downstream biological event in chromatin.