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23 pages, 2537 KiB

Open AccessArticle

VPS72/YL1-Mediated H2A.Z Deposition Is Required for Nuclear Reassembly after Mitosis

by Daniel Moreno-Andrés, Hideki Yokoyama, Anja Scheufen, Guillaume Holzer, Hongqi Lue, Anna Katharina Schellhaus, Marion Weberruss, Masatoshi Takagi and Wolfram Antonin

Cells 2020, 9(7), 1702; https://doi.org/10.3390/cells9071702 - 16 Jul 2020

Cited by 11 | Viewed by 4759

Abstract

The eukaryotic nucleus remodels extensively during mitosis. Upon mitotic entry, the nuclear envelope breaks down and chromosomes condense into rod-shaped bodies, which are captured by the spindle apparatus and segregated during anaphase. Through telophase, chromosomes decondense and the nuclear envelope reassembles, leading to [...] Read more.

The eukaryotic nucleus remodels extensively during mitosis. Upon mitotic entry, the nuclear envelope breaks down and chromosomes condense into rod-shaped bodies, which are captured by the spindle apparatus and segregated during anaphase. Through telophase, chromosomes decondense and the nuclear envelope reassembles, leading to a functional interphase nucleus. While the molecular processes occurring in early mitosis are intensively investigated, our knowledge about molecular mechanisms of nuclear reassembly is rather limited. Using cell free and cellular assays, we identify the histone variant H2A.Z and its chaperone VPS72/YL1 as important factors for reassembly of a functional nucleus after mitosis. Live-cell imaging shows that siRNA-mediated downregulation of VPS72 extends the telophase in HeLa cells. In vitro, depletion of VPS72 or H2A.Z results in malformed and nonfunctional nuclei. VPS72 is part of two chromatin-remodeling complexes, SRCAP and EP400. Dissecting the mechanism of nuclear reformation using cell-free assays, we, however, show that VPS72 functions outside of the SRCAP and EP400 remodeling complexes to deposit H2A.Z, which in turn is crucial for formation of a functional nucleus. Full article

(This article belongs to the Special Issue Histone Variants from Structure to Molecular Function)

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17 pages, 1973 KiB

Open AccessArticle

The Histone Variant MacroH2A1 Regulates Key Genes for Myogenic Cell Fusion in a Splice-Isoform Dependent Manner

by Sarah Hurtado-Bagès, Melanija Posavec Marjanovic, Vanesa Valero, Roberto Malinverni, David Corujo, Philippe Bouvet, Anne-Claire Lavigne, Kerstin Bystricky and Marcus Buschbeck

Cells 2020, 9(5), 1109; https://doi.org/10.3390/cells9051109 - 30 Apr 2020

Cited by 7 | Viewed by 4141

Abstract

MacroH2A histone variants have functions in differentiation, somatic cell reprogramming and cancer. However, at present, it is not clear how macroH2As affect gene regulation to exert these functions. We have parted from the initial observation that loss of total macroH2A1 led to a [...] Read more.

MacroH2A histone variants have functions in differentiation, somatic cell reprogramming and cancer. However, at present, it is not clear how macroH2As affect gene regulation to exert these functions. We have parted from the initial observation that loss of total macroH2A1 led to a change in the morphology of murine myotubes differentiated ex vivo. The fusion of myoblasts to myotubes is a key process in embryonic myogenesis and highly relevant for muscle regeneration after acute or chronic injury. We have focused on this physiological process, to investigate the functions of the two splice isoforms of macroH2A1. Individual perturbation of the two isoforms in myotubes forming in vitro from myogenic C2C12 cells showed an opposing phenotype, with macroH2A1.1 enhancing, and macroH2A1.2 reducing, fusion. Differential regulation of a subset of fusion-related genes encoding components of the extracellular matrix and cell surface receptors for adhesion correlated with these phenotypes. We describe, for the first time, splice isoform-specific phenotypes for the histone variant macroH2A1 in a physiologic process and provide evidence for a novel underlying molecular mechanism of gene regulation. Full article

(This article belongs to the Special Issue Histone Variants from Structure to Molecular Function)

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14 pages, 3884 KiB

Open AccessArticle

RNA-Guided Genomic Localization of H2A.L.2 Histone Variant

by Naghmeh Hoghoughi, Sophie Barral, Sandrine Curtet, Florent Chuffart, Guillaume Charbonnier, Denis Puthier, Thierry Buchou, Sophie Rousseaux and Saadi Khochbin

Cells 2020, 9(2), 474; https://doi.org/10.3390/cells9020474 - 18 Feb 2020

Cited by 11 | Viewed by 3154

Abstract

The molecular basis of residual histone retention after the nearly genome-wide histone-to-protamine replacement during late spermatogenesis is a critical and open question. Our previous investigations showed that in postmeiotic male germ cells, the genome-scale incorporation of histone variants TH2B-H2A.L.2 allows a controlled replacement [...] Read more.

The molecular basis of residual histone retention after the nearly genome-wide histone-to-protamine replacement during late spermatogenesis is a critical and open question. Our previous investigations showed that in postmeiotic male germ cells, the genome-scale incorporation of histone variants TH2B-H2A.L.2 allows a controlled replacement of histones by protamines to occur. Here, we highlight the intrinsic ability of H2A.L.2 to specifically target the pericentric regions of the genome and discuss why pericentric heterochromatin is a privileged site of histone retention in mature spermatozoa. We observed that the intranuclear localization of H2A.L.2 is controlled by its ability to bind RNA, as well as by an interplay between its RNA-binding activity and its tropism for pericentric heterochromatin. We identify the H2A.L.2 RNA-binding domain and demonstrate that in somatic cells, the replacement of H2A.L.2 RNA-binding motif enhances and stabilizes its pericentric localization, while the forced expression of RNA increases its homogenous nuclear distribution. Based on these data, we propose that the specific accumulation of RNA on pericentric regions combined with H2A.L.2 tropism for these regions are responsible for stabilizing H2A.L.2 on these regions in mature spermatozoa. This situation would favor histone retention on pericentric heterochromatin. Full article

(This article belongs to the Special Issue Histone Variants from Structure to Molecular Function)

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Review

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22 pages, 1155 KiB

Open AccessReview

Histone Variant H3.3 Mutations in Defining the Chromatin Function in Mammals

by Matteo Trovato, Vibha Patil, Maja Gehre and Kyung Min Noh

Cells 2020, 9(12), 2716; https://doi.org/10.3390/cells9122716 - 18 Dec 2020

Cited by 8 | Viewed by 4596

Abstract

The systematic mutation of histone 3 (H3) genes in model organisms has proven to be a valuable tool to distinguish the functional role of histone residues. No system exists in mammalian cells to directly manipulate canonical histone H3 due to a large number [...] Read more.

The systematic mutation of histone 3 (H3) genes in model organisms has proven to be a valuable tool to distinguish the functional role of histone residues. No system exists in mammalian cells to directly manipulate canonical histone H3 due to a large number of clustered and multi-loci histone genes. Over the years, oncogenic histone mutations in a subset of H3 have been identified in humans, and have advanced our understanding of the function of histone residues in health and disease. The oncogenic mutations are often found in one allele of the histone variant H3.3 genes, but they prompt severe changes in the epigenetic landscape of cells, and contribute to cancer development. Therefore, mutation approaches using H3.3 genes could be relevant to the determination of the functional role of histone residues in mammalian development without the replacement of canonical H3 genes. In this review, we describe the key findings from the H3 mutation studies in model organisms wherein the genetic replacement of canonical H3 is possible. We then turn our attention to H3.3 mutations in human cancers, and discuss H3.3 substitutions in the N-terminus, which were generated in order to explore the specific residue or associated post-translational modification. Full article

(This article belongs to the Special Issue Histone Variants from Structure to Molecular Function)

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11 pages, 1402 KiB

Open AccessReview

The Role of Histone Variants in the Epithelial-To-Mesenchymal Transition

by Imtiaz Nisar Lone, Burcu Sengez, Ali Hamiche, Stefan Dimitrov and Hani Alotaibi

Cells 2020, 9(11), 2499; https://doi.org/10.3390/cells9112499 - 17 Nov 2020

Cited by 1 | Viewed by 3143

Abstract

The epithelial-to-mesenchymal transition (EMT) is a physiological process activated during early embryogenesis, which continues to shape tissues and organs later on. It is also hijacked by tumor cells during metastasis. The regulation of EMT has been the focus of many research groups culminating [...] Read more.

The epithelial-to-mesenchymal transition (EMT) is a physiological process activated during early embryogenesis, which continues to shape tissues and organs later on. It is also hijacked by tumor cells during metastasis. The regulation of EMT has been the focus of many research groups culminating in the last few years and resulting in an elaborate transcriptional network buildup. However, the implication of epigenetic factors in the control of EMT is still in its infancy. Recent discoveries pointed out that histone variants, which are key epigenetic players, appear to be involved in EMT control. This review summarizes the available data on histone variants’ function in EMT that would contribute to a better understanding of EMT itself and EMT-related diseases. Full article

(This article belongs to the Special Issue Histone Variants from Structure to Molecular Function)

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31 pages, 3409 KiB

Open AccessReview

Histone Variants: Guardians of Genome Integrity

by Juliette Ferrand, Beatrice Rondinelli and Sophie E. Polo

Cells 2020, 9(11), 2424; https://doi.org/10.3390/cells9112424 - 05 Nov 2020

Cited by 25 | Viewed by 6575

Abstract

Chromatin integrity is key for cell homeostasis and for preventing pathological development. Alterations in core chromatin components, histone proteins, recently came into the spotlight through the discovery of their driving role in cancer. Building on these findings, in this review, we discuss how [...] Read more.

Chromatin integrity is key for cell homeostasis and for preventing pathological development. Alterations in core chromatin components, histone proteins, recently came into the spotlight through the discovery of their driving role in cancer. Building on these findings, in this review, we discuss how histone variants and their associated chaperones safeguard genome stability and protect against tumorigenesis. Accumulating evidence supports the contribution of histone variants and their chaperones to the maintenance of chromosomal integrity and to various steps of the DNA damage response, including damaged chromatin dynamics, DNA damage repair, and damage-dependent transcription regulation. We present our current knowledge on these topics and review recent advances in deciphering how alterations in histone variant sequence, expression, and deposition into chromatin fuel oncogenic transformation by impacting cell proliferation and cell fate transitions. We also highlight open questions and upcoming challenges in this rapidly growing field. Full article

(This article belongs to the Special Issue Histone Variants from Structure to Molecular Function)

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21 pages, 2631 KiB

Open AccessReview

Deciphering the Enigma of the Histone H2A.Z-1/H2A.Z-2 Isoforms: Novel Insights and Remaining Questions

by Manjinder S. Cheema, Katrina V. Good, Bohyun Kim, Heddy Soufari, Connor O’Sullivan, Melissa E. Freeman, Gilda Stefanelli, Ciro Rivera Casas, Kristine E. Zengeler, Andrew J. Kennedy, Jose Maria Eirin Lopez, Perry L. Howard, Iva B. Zovkic, Jeffrey Shabanowitz, Deanna D. Dryhurst, Donald F. Hunt, Cameron D. Mackereth and Juan Ausió

Cells 2020, 9(5), 1167; https://doi.org/10.3390/cells9051167 - 08 May 2020

Cited by 4 | Viewed by 3915

Abstract

The replication independent (RI) histone H2A.Z is one of the more extensively studied variant members of the core histone H2A family, which consists of many replication dependent (RD) members. The protein has been shown to be indispensable for survival, and involved in multiple [...] Read more.

The replication independent (RI) histone H2A.Z is one of the more extensively studied variant members of the core histone H2A family, which consists of many replication dependent (RD) members. The protein has been shown to be indispensable for survival, and involved in multiple roles from DNA damage to chromosome segregation, replication, and transcription. However, its functional involvement in gene expression is controversial. Moreover, the variant in several groups of metazoan organisms consists of two main isoforms (H2A.Z-1 and H2A.Z-2) that differ in a few (3–6) amino acids. They comprise the main topic of this review, starting from the events that led to their identification, what is currently known about them, followed by further experimental, structural, and functional insight into their roles. Despite their structural differences, a direct correlation to their functional variability remains enigmatic. As all of this is being elucidated, it appears that a strong functional involvement of isoform variability may be connected to development. Full article

(This article belongs to the Special Issue Histone Variants from Structure to Molecular Function)

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12 pages, 2340 KiB

Open AccessReview

Short Histone H2A Variants: Small in Stature but not in Function

by Xuanzhao Jiang, Tatiana A. Soboleva and David J. Tremethick

Cells 2020, 9(4), 867; https://doi.org/10.3390/cells9040867 - 02 Apr 2020

Cited by 14 | Viewed by 3711

Abstract

The dynamic packaging of DNA into chromatin regulates all aspects of genome function by altering the accessibility of DNA and by providing docking pads to proteins that copy, repair and express the genome. Different epigenetic-based mechanisms have been described that alter the way [...] Read more.

The dynamic packaging of DNA into chromatin regulates all aspects of genome function by altering the accessibility of DNA and by providing docking pads to proteins that copy, repair and express the genome. Different epigenetic-based mechanisms have been described that alter the way DNA is organised into chromatin, but one fundamental mechanism alters the biochemical composition of a nucleosome by substituting one or more of the core histones with their variant forms. Of the core histones, the largest number of histone variants belong to the H2A class. The most divergent class is the designated “short H2A variants” (H2A.B, H2A.L, H2A.P and H2A.Q), so termed because they lack a H2A C-terminal tail. These histone variants appeared late in evolution in eutherian mammals and are lineage-specific, being expressed in the testis (and, in the case of H2A.B, also in the brain). To date, most information about the function of these peculiar histone variants has come from studies on the H2A.B and H2A.L family in mice. In this review, we describe their unique protein characteristics, their impact on chromatin structure, and their known functions plus other possible, even non-chromatin, roles in an attempt to understand why these peculiar histone variants evolved in the first place. Full article

(This article belongs to the Special Issue Histone Variants from Structure to Molecular Function)

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14 pages, 1599 KiB

Open AccessReview

Job Opening for Nucleosome Mechanic: Flexibility Required

by Mary Pitman, Daniël P. Melters and Yamini Dalal

Cells 2020, 9(3), 580; https://doi.org/10.3390/cells9030580 - 01 Mar 2020

Cited by 6 | Viewed by 3790

Abstract

The nucleus has been studied for well over 100 years, and chromatin has been the intense focus of experiments for decades. In this review, we focus on an understudied aspect of chromatin biology, namely the chromatin fiber polymer’s mechanical properties. In recent years, [...] Read more.

The nucleus has been studied for well over 100 years, and chromatin has been the intense focus of experiments for decades. In this review, we focus on an understudied aspect of chromatin biology, namely the chromatin fiber polymer’s mechanical properties. In recent years, innovative work deploying interdisciplinary approaches including computational modeling, in vitro manipulations of purified and native chromatin have resulted in deep mechanistic insights into how the mechanics of chromatin might contribute to its function. The picture that emerges is one of a nucleus that is shaped as much by external forces pressing down upon it, as internal forces pushing outwards from the chromatin. These properties may have evolved to afford the cell a dynamic and reversible force-induced communication highway which allows rapid coordination between external cues and internal genomic function. Full article

(This article belongs to the Special Issue Histone Variants from Structure to Molecular Function)

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