International Journal of Molecular Sciences Review Replication-Coupled Chromatin Remodeling: An Overview of Disassembly and Assembly of Chromatin during Replication Céline Duc and Christophe Thiriet * UFIP UMR-CNRS 6286, Épigénétique et Dynamique de la Chromatine, Université de Nantes, 2 rue de la Houssinière, 44322 Nantes, France; [email protected] * Correspondence: [email protected] Abstract: The doubling of genomic DNA during the S-phase of the cell cycle involves the global remodeling of chromatin at replication forks. The present review focuses on the eviction of nucle- osomes in front of the replication forks to facilitate the passage of replication machinery and the mechanism of replication-coupled chromatin assembly behind the replication forks. The recycling of parental histones as well as the nuclear import and the assembly of newly synthesized histones are also discussed with regard to the epigenetic inheritance. Keywords: replication; chromatin; histones 1. Introduction The doubling of genomic DNA occurring in the S-phase involves a timely regulated remodeling of the entire chromatin. Indeed, each replication site requires the displacement of nucleosomes in front of the fork to enable the progression of the replication machinery Citation: Duc, C.; Thiriet, C. and the reformation of chromatin behind the replication fork [1,2]. The mechanism of Replication-Coupled Chromatin histone eviction to facilitate the progression of the replication and replication-coupled Remodeling: An Overview of chromatin assembly with parental and newly synthesized histones is conserved through Disassembly and Assembly of the entire eukaryotic kingdom [2]. The histones are the most abundant proteins in the Chromatin during Replication. Int. J. nucleus. It is generally believed that they have a dual function in eukaryotes, which consists Mol. Sci. 2021, 22, 1113. https:// of DNA packaging and regulation of DNA accessibility [3]. The histones are divided into doi.org/10.3390/ijms22031113 five distinct major subtypes: the core histones, H2A, H2B, H3 and H4, and the linker histone, H1 [3,4]. In chromatin, the core histones form a tripartite octamer composed of Academic Editor: Ralf Blossey two of each H2A, H2B, H3 and H4, wherein H3 and H4 are the central tetramers flanked Received: 23 December 2020 by two dimers of H2A and H2B and wrapped by ~146 base pairs, forming therefore the Accepted: 20 January 2021 Published: 23 January 2021 nucleosome [5,6]. The fifth histone subtype is associated with extra DNA at the outer face of the nucleosome to generate the chromatosome [4,7] (Figure1). The linker histone Publisher’s Note: MDPI stays neutral contributes to the higher-order structure of chromatin within the nucleus [8–10]. with regard to jurisdictional claims in The formation of nucleoprotein structures between histones and DNA facilitates the published maps and institutional affil- organization of the eukaryotic genome within the nucleus. Moreover, the histones and, iations. specifically, the amino-terminal tails of core histones are subjected to post-translational modifications, which are involved in genetic regulation [11,12]. Hence, it has been proposed that the variety of core histone modifications might constitute epigenetic signatures that continuously remodel chromatin for generating the molecular environment that enhances or impedes the accessibility of cellular machineries to DNA [13,14]. Three main types of Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. actors are involved in the dynamics of these modifications [15]. Their deposition is per- This article is an open access article formed by enzymes: the writers. When the histone is modified, the added mark is involved distributed under the terms and in the recruitment of specific chromatin factors: the readers. While the epigenetic modifica- conditions of the Creative Commons tions of histones contribute to chromatin dynamics and remodeling, these modifications Attribution (CC BY) license (https:// are transient and require enzymes for their removal: the erasers. Even though the core creativecommons.org/licenses/by/ histone tail modifications directly affect the chromatin activities, most modifications are not 4.0/). exclusive and require a combinatorial set of post-translational modifications for revealing Int. J. Mol. Sci. 2021, 22, 1113. https://doi.org/10.3390/ijms22031113 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 11 Int. J. Mol. Sci. 2021, 22, 1113 the core histone tail modifications directly affect the chromatin activities, most modifica-2 of 11 tions are not exclusive and require a combinatorial set of post-translational modifications for revealing biological functions, which led to the proposal that the post-translational modifications of core histones might constitute an epigenetic code [13,16]. Thus, the core biological functions, which led to the proposal that the post-translational modifications histone tail domains are critical regulators of chromatin activities. of core histones might constitute an epigenetic code [13,16]. Thus, the core histone tail domains are critical regulators of chromatin activities. FigureFigure 1. 1.TerminologyTerminology of the of thehistone histone and and nucleoprotei nucleoproteinn complexes. complexes. The drawing The drawing represents represents the the proteinsproteins and and nucleoprotein nucleoprotein complexes complexes that that compose compose the thebasic basic unit unitof chromatin. of chromatin. H4 (1); H4 H3 (1); (2); H3 (2); H2BH2B (3); (3); H2AH2A (4) (4) (Core (Core histones); histones); H3/H4 H3/H4 dimer dimer (5); (H3/H4) (5); (H3/H4) 2 tetramer 2 tetramer (6), H2A/H2B (6), H2A/H2B dimer dimer(7) (7) (histone(histone complexes); complexes); core core particle particle (8) (8) (146 (146 bp bp of of DNA); DNA); nucleosome nucleosome (9) (9) (>146 (>146 bp bp of of DNA, DNA, presence presence of of linkerlinker DNA);DNA); chromatosomechromatosome (11)(11) (nucleosome(nucleosome with with linker linker histone histone (10)). (10)). Importantly,Importantly, during during the the S-phase S-phase of of the the cell cell cycle, cycle, the the replication replication implies implies the the doubling doubling ofof the the amount amount of ofDNA DNA within within the the nucleus nucleus [17] [17. ].Hence, Hence, to to preserve preserve the the compaction compaction of of the the geneticgenetic information, information, novel novel histones histones areare required.required. While While DNA DNA replication replication occurs occurs exclusively exclu- sivelywithin within the nucleus, the nucleus, histone histone synthesis synthesis involves involves several several steps, steps, such such as the as transcriptionthe transcrip- of tionthe of histone the histone genes, genes, the cytoplasmicthe cytoplasmic translation translation of histoneof histone RNAs, RNAs, the the nuclear nuclear import import of ofneo-synthesized neo-synthesized histones histones and and their their assembly assembly within within chromatin. chromatin. The The nucleosome nucleosome requires re- the four core histone proteins; the histone sequences present variations [18–21]. These quires the four core histone proteins; the histone sequences present variations [18–21]. isoforms are associated with specific chromatin processes such as transcription control, These isoforms are associated with specific chromatin processes such as transcription con- DNA repair or regulation of centromeric heterochromatin [20–24]. In addition to the trol, DNA repair or regulation of centromeric heterochromatin [20–24]. In addition to the variations in sequences, the histone variants differ from the canonical histone in their variationstiming of in synthesis sequences, [25 the,26 histone]. Indeed, variants canonical differ core from histone the canonical syntheses histone are controlledin their tim- by ingthe of cellsynthesis cycle and[25,26]. are Ind producedeed, canonical only during core histone the S-phase, syntheses which are controlled led to their by definition the cell cycleas replication-dependent and are produced only histones. during the In contrast,S-phase, thewhich core led histone to their variants definition are synthesizedas replica- tion-dependentthroughout the histones. interphase In contrast, and are definedthe core ashistone replication-independent variants are synthesized histones. throughout the interphaseThe complex and are mechanism defined as of replication-independent chromatin duplication has histones. been extensively studied over theThe past complex few decades. mechanism Chromatin of chromatin replication duplic involvesation thehas remodeling been extensively of the studied entire genome over theonce past per few cell decades. cycle toChromatin facilitate replication the passage involves of replication the remodeling machinery of andthe entire the reassembly genome of nucleosomes behind the replication fork. The focus of this review is to summarize and discuss the current knowledge on the processes occurring in front of and behind the replication fork. Here, we emphasize the histone processing rather than the bevy of chaperones and factors involved (see for review [27–30]). Int. J. Mol. Sci. 2021, 22, 1113 3 of 11 2. Chromatin Remodeling in Front of the Replication Fork Chromatin replication is a timely regulated process, wherein the chromatin structure presents a hindrance to the cellular machinery. Thus, it is first required to withdraw the higher-order chromatin structure. The chromatin