Knockout tales: the versatile roles of histone H3.3 in development and disease

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Abstract

Histone variant H3.3 plays novel roles in development as compared to canonical H3 proteins and is the most commonly mutated histone protein of any kind in human disease. Here we discuss how gene targeting studies of the two H3.3-coding genes H3f3a and H3f3b have provided important insights into H3.3 functions including in gametes as well as brain and lung development. Knockouts have also provided insights into the important roles of H3.3 in maintaining genomic stability and chromatin organization, processes that are also affected when H3.3 is mutated in human diseases such as pediatric tumors and neurodevelopmental syndromes. Overall, H3.3 is a unique histone linking development and disease via epigenomic machinery.

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Most cited references 51

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Regulation of chromatin by histone modifications.

Andrew Bannister, Tony Kouzarides (2011)

Chromatin is not an inert structure, but rather an instructive DNA scaffold that can respond to external cues to regulate the many uses of DNA. A principle component of chromatin that plays a key role in this regulation is the modification of histones. There is an ever-growing list of these modifications and the complexity of their action is only just beginning to be understood. However, it is clear that histone modifications play fundamental roles in most biological processes that are involved in the manipulation and expression of DNA. Here, we describe the known histone modifications, define where they are found genomically and discuss some of their functional consequences, concentrating mostly on transcription where the majority of characterisation has taken place.

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Crystal structure of the nucleosome core particle at 2.8 A resolution.

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The X-ray crystal structure of the nucleosome core particle of chromatin shows in atomic detail how the histone protein octamer is assembled and how 146 base pairs of DNA are organized into a superhelix around it. Both histone/histone and histone/DNA interactions depend on the histone fold domains and additional, well ordered structure elements extending from this motif. Histone amino-terminal tails pass over and between the gyres of the DNA superhelix to contact neighbouring particles. The lack of uniformity between multiple histone/DNA-binding sites causes the DNA to deviate from ideal superhelix geometry.

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Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.

Jeremy Schwartzentruber, Andrey Korshunov, Xiao-Yang Liu … (2012)

Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.

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Author and article information

Contributors

Paul S. Knoepfler: knoepfler@ucdavis.edu

Journal

Journal ID (nlm-ta): Epigenetics Chromatin

Journal ID (iso-abbrev): Epigenetics Chromatin

Title: Epigenetics & Chromatin

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8935

Publication date (Electronic): 10 October 2023

Publication date PMC-release: 10 October 2023

Publication date Collection: 2023

Volume: 16

Electronic Location Identifier: 38

Affiliations

[1 ]Department of Cell Biology and Human Anatomy, University of California Davis, ( https://ror.org/05rrcem69) Davis, CA 95616 USA

[2 ]GRID grid.415852.f, ISNI 0000 0004 0449 5792, Institute for Pediatric Regenerative Medicine, , Shriners Hospital for Children Northern California, ; Sacramento, CA 95817 USA

[3 ]Genome Center, University of California Davis, ( https://ror.org/05rrcem69) Davis, CA 95616 USA

Article

Publisher ID: 512

DOI: 10.1186/s13072-023-00512-8

PMC ID: 10563256

PubMed ID: 37814296

SO-VID: fa49b98d-54f8-45f8-a178-a89d03a87318

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 11 August 2023

Date accepted : 4 October 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: 1R01NS106878

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: histone h3.3,h3f3a,h3f3b,mouse knockouts

Data availability:

ScienceOpen disciplines: Genetics

Keywords: histone h3.3, h3f3a, h3f3b, mouse knockouts

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Knockout tales: the versatile roles of histone H3.3 in development and disease

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Abstract

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Most cited references 51

Regulation of chromatin by histone modifications.

Crystal structure of the nucleosome core particle at 2.8 A resolution.

Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.

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