CAF-1 and Rtt101p function within the replication-coupled chromatin assembly network to promote H4 K16ac, preventing ectopic silencing.

Robert Schneider,Tiffany J Young,Claire Pfeffer,Wenjie Liu,Joseph Irudayaraj,Yi Cui,Emilie Hobbs,Ann L Kirchmaier

doi:10.1371/journal.pgen.1009226

Abstract

Replication-coupled chromatin assembly is achieved by a network of alternate pathways containing different chromatin assembly factors and histone-modifying enzymes that coordinate deposition of nucleosomes at the replication fork. Here we describe the organization of a CAF-1-dependent pathway in Saccharomyces cerevisiae that regulates acetylation of histone H4 K16. We demonstrate factors that function in this CAF-1-dependent pathway are important for preventing establishment of silenced states at inappropriate genomic sites using a crippled HMR locus as a model, while factors specific to other assembly pathways do not. This CAF-1-dependent pathway required the cullin Rtt101p, but was functionally distinct from an alternate pathway involving Rtt101p-dependent ubiquitination of histone H3 and the chromatin assembly factor Rtt106p. A major implication from this work is that cells have the inherent ability to create different chromatin modification patterns during DNA replication via differential processing and deposition of histones by distinct chromatin assembly pathways within the network.

Highlights

Replication-coupled chromatin assembly is a multi-step, multi-pathway process coordinated by histone modifying proteins, histone chaperones, and replication factors
Replication-coupled chromatin assembly occurs via a network of alternate pathways through which histones are processed, and chromatin is disassembled in front of the replication fork, reassembled behind the fork to ensure the inheritance of appropriate epigenetic states
CAF-1 and Rtt101 affect silencing via H4 K16ac

Summary

Introduction

Replication-coupled chromatin assembly is a multi-step, multi-pathway process coordinated by histone modifying proteins, histone chaperones, and replication factors. Daxx contains a Rtt106p-like acidic domain and acts as a H3-H4 histone chaperone, but current evidence shows that Daxx binds to the mammalian replication-independent deposition H3 histone variant H3.3, rather than the replication-coupled variant H3.1, and functions only in replication-independent chromatin assembly [4,10]. Our understanding of the interactions that occur within this network of replication-coupled H3-H4 nucleosome assembly pathways, how these interactions are regulated, and, in turn, influence histone modification patterns remains limited. Defects in these pathways do result in altered histone modification patterns across the genome, defects in epigenetic processes, and altered responses to a variety of stressors ranging from oxidative stress to DNA damage [13,14,15,16,17,18]

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Conclusion