title: Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for the epigenetic inheritance of DNA methylation.
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.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Rothbart
authors.forename: Bradley M
authors.initials: BM
authors.lastname: Dickson
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Ong
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Krajewski
authors.forename: Scott
authors.initials: S
authors.lastname: Houliston
authors.forename: Dmitri B
authors.initials: DB
authors.lastname: Kireev
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.forename: Brian D
authors.initials: BD
authors.lastname: Strahl
mesh_terms: D022762:CCAAT-Enhancer-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D006570:Heterochromatin; D006657:Histones; D018398:Homeodomain Proteins; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: DNA methylation; DNMT1; UHRF1; epigenetic inheritance; histone code; multivalency