Targeting neuronal epigenomes for brain rejuvenation

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Abstract

Aging is associated with a progressive decline of brain function, and the underlying causes and possible interventions to prevent this cognitive decline have been the focus of intense investigation. The maintenance of neuronal function over the lifespan requires proper epigenetic regulation, and accumulating evidence suggests that the deterioration of the neuronal epigenetic landscape contributes to brain dysfunction during aging. Epigenetic aging of neurons may, however, be malleable. Recent reports have shown age-related epigenetic changes in neurons to be reversible and targetable by rejuvenation strategies that can restore brain function during aging. This review discusses the current evidence that identifies neuronal epigenetic aging as a driver of cognitive decline and a promising target of brain rejuvenation strategies, and it highlights potential approaches for the specific manipulation of the aging neuronal epigenome to restore a youthful epigenetic state in the brain.

Abstract

This review discusses neuronal epigenetic aging as a driver of cognitive decline with age and highlights potential interventions for targeted brain rejuvenation.

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DNA methylation age of human tissues and cell types

Steve Horvath, Ilias Lagkouvardos (2014)

Background It is not yet known whether DNA methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulting age prediction is a biologically meaningful measure. Results I developed a multi-tissue predictor of age that allows one to estimate the DNA methylation age of most tissues and cell types. The predictor, which is freely available, was developed using 8,000 samples from 82 Illumina DNA methylation array datasets, encompassing 51 healthy tissues and cell types. I found that DNA methylation age has the following properties: first, it is close to zero for embryonic and induced pluripotent stem cells; second, it correlates with cell passage number; third, it gives rise to a highly heritable measure of age acceleration; and, fourth, it is applicable to chimpanzee tissues. Analysis of 6,000 cancer samples from 32 datasets showed that all of the considered 20 cancer types exhibit significant age acceleration, with an average of 36 years. Low age-acceleration of cancer tissue is associated with a high number of somatic mutations and TP53 mutations, while mutations in steroid receptors greatly accelerate DNA methylation age in breast cancer. Finally, I characterize the 353 CpG sites that together form an aging clock in terms of chromatin states and tissue variance. Conclusions I propose that DNA methylation age measures the cumulative effect of an epigenetic maintenance system. This novel epigenetic clock can be used to address a host of questions in developmental biology, cancer and aging research.

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Ageing as a risk factor for neurodegenerative disease

Yujun Hou, Xiuli Dan, Mansi Babbar … (2019)

Ageing is the primary risk factor for most neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD). One in ten individuals aged ≥65 years has AD and its prevalence continues to increase with increasing age. Few or no effective treatments are available for ageing-related neurodegenerative diseases, which tend to progress in an irreversible manner and are associated with large socioeconomic and personal costs. This Review discusses the pathogenesis of AD, PD and other neurodegenerative diseases, and describes their associations with the nine biological hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication. The central biological mechanisms of ageing and their potential as targets of novel therapies for neurodegenerative diseases are also discussed, with potential therapies including NAD+ precursors, mitophagy inducers and inhibitors of cellular senescence.

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Epigenome editing by a CRISPR/Cas9-based acetyltransferase activates genes from promoters and enhancers

Isaac B. Hilton, Anthony M. D’Ippolito, Christopher M. Vockley … (2015)

Technologies that facilitate the targeted manipulation of epigenetic marks could be used to precisely control cell phenotype or interrogate the relationship between the epigenome and transcriptional control. Here we have generated a programmable acetyltransferase based on the CRISPR/Cas9 gene regulation system, consisting of the nuclease-null dCas9 protein fused to the catalytic core of the human acetyltransferase p300. This fusion protein catalyzes acetylation of histone H3 lysine 27 at its target sites, corresponding with robust transcriptional activation of target genes from promoters, proximal enhancers, and distal enhancers. Gene activation by the targeted acetyltransferase is highly specific across the genome. In contrast to conventional dCas9-based activators, the acetyltransferase effectively activates genes from enhancer regions and with individual guide RNAs. The core p300 domain is also portable to other programmable DNA-binding proteins. These results support targeted acetylation as a causal mechanism of transactivation and provide a new robust tool for manipulating gene regulation.

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Author and article information

Contributors

Sara Zocher:

ORCID: http://orcid.org/0000-0001-8211-5490

sara.zocher@dzne.de

Journal

Journal ID (nlm-ta): EMBO J

Journal ID (iso-abbrev): EMBO J

Title: The EMBO Journal

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 0261-4189

ISSN (Electronic): 1460-2075

Publication date (Electronic): 15 July 2024

Publication date PMC-release: 15 July 2024

Publication date Collection: August 2024

Volume: 43

Issue: 16

Pages: 3312-3326

Affiliations

German Center for Neurodegenerative Diseases, ( https://ror.org/043j0f473) Tatzberg 41, 01307 Dresden, Germany

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Sara Zocher http://orcid.org/0000-0001-8211-5490

Article

Publisher ID: 148

DOI: 10.1038/s44318-024-00148-8

PMC ID: 11329789

PubMed ID: 39009672

SO-VID: ee4b2e64-9615-4b7f-9d62-c5e1bea7c37c

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/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible.

History

Date received : 23 February 2024

Date revision received : 21 May 2024

Date accepted : 28 May 2024

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100008662, Joachim Herz Stiftung (Joachim Herz Foundation);

Award ID: Add-on fellowship

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ScienceOpen disciplines: Molecular biology

Keywords: neuron aging,cognitive decline,neuronal epigenome,epigenetic rejuvenation,epigenome editing,chromatin, transcription & genomics,molecular biology of disease,neuroscience

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ScienceOpen disciplines: Molecular biology

Keywords: neuron aging, cognitive decline, neuronal epigenome, epigenetic rejuvenation, epigenome editing, chromatin, transcription & genomics, molecular biology of disease, neuroscience

Targeting neuronal epigenomes for brain rejuvenation

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Neuronal Signaling

Most cited references 165

DNA methylation age of human tissues and cell types

Ageing as a risk factor for neurodegenerative disease

Epigenome editing by a CRISPR/Cas9-based acetyltransferase activates genes from promoters and enhancers

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