Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions.

Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.
Cell (Impact Factor: 33.12). 05/2011; 145(5):692-706. DOI: 10.1016/j.cell.2011.03.053
Source: PubMed

ABSTRACT Little is known about how combinations of histone marks are interpreted at the level of nucleosomes. The second PHD finger of human BPTF is known to specifically recognize histone H3 when methylated on lysine 4 (H3K4me2/3). Here, we examine how additional heterotypic modifications influence BPTF binding. Using peptide surrogates, three acetyllysine ligands are indentified for a PHD-adjacent bromodomain in BPTF via systematic screening and biophysical characterization. Although the bromodomain displays limited discrimination among the three possible acetyllysines at the peptide level, marked selectivity is observed for only one of these sites, H4K16ac, in combination with H3K4me3 at the mononucleosome level. In support, these two histone marks constitute a unique trans-histone modification pattern that unambiguously resides within a single nucleosomal unit in human cells, and this module colocalizes with these marks in the genome. Together, our data call attention to nucleosomal patterning of covalent marks in dictating critical chromatin associations.

Download full-text


Available from: Haitao Li, Feb 23, 2015
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Heterochromatin is a barrier to DNA repair that correlates strongly with elevated somatic mutation in cancer. CHD class II nucleosome remodeling activity (specifically CHD3.1) retained by KAP-1 increases heterochromatin compaction and impedes DNA double-strand break (DSB) repair requiring Artemis. This obstruction is alleviated by chromatin relaxation via ATM-dependent KAP-1S824 phosphorylation (pKAP-1) and CHD3.1 dispersal from heterochromatic DSBs; however, how heterochromatin compaction is actually adjusted after CHD3.1 dispersal is unknown. In this paper, we demonstrate that Artemis-dependent DSB repair in heterochromatin requires ISWI (imitation switch)-class ACF1-SNF2H nucleosome remodeling. Compacted chromatin generated by CHD3.1 after DNA replication necessitates ACF1-SNF2H-mediated relaxation for DSB repair. ACF1-SNF2H requires RNF20 to bind heterochromatic DSBs, underlies RNF20-mediated chromatin relaxation, and functions downstream of pKAP-1-mediated CHD3.1 dispersal to enable DSB repair. CHD3.1 and ACF1-SNF2H display counteractive activities but similar histone affinities (via the plant homeodomains of CHD3.1 and ACF1), which we suggest necessitates a two-step dispersal and recruitment system regulating these opposing chromatin remodeling activities during DSB repair. © 2014 Klement et al.
    The Journal of Cell Biology 12/2014; 207(6):717-733. DOI:10.1083/jcb.201405077 · 9.69 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A multi-layered set of epigenetic marks, including post-translational modifications of histones and methylation of DNA, is finely tuned to define the epigenetic state of chromatin in any given cell type under specific conditions. Recently, the knowledge about the combinations of epigenetic marks occurring in the genome of different cell types under various conditions is rapidly increasing. Computational methods were developed for the identification of these states, unraveling the combinatorial nature of epigenetic marks and their association to genomic functional elements and transcriptional states. Nevertheless, the precise rules defining the interplay between all these marks remain poorly characterized. In this perspective we review the current state of this research field, illustrating the power and the limitations of current approaches. Finally, we sketch future avenues of research illustrating how the adoption of specific experimental designs coupled with available experimental approaches could be critical for a significant progress in this area.
    Frontiers in Genetics 09/2014; 5:335. DOI:10.3389/fgene.2014.00335