Format

Send to

Choose Destination
Genome Biol. 2019 Aug 14;20(1):146. doi: 10.1186/s13059-019-1753-9.

Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1.

Author information

1
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. dem44@ebi.ac.uk.
2
Chronomics Ltd., Cambridge, UK. dem44@ebi.ac.uk.
3
Department of Pathology and Laboratory Medicine, Western University, London, Canada.
4
Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, Canada.
5
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
6
European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
7
Chronomics Ltd., Cambridge, UK.
8
Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Canada.
9
Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
10
Epigenetics Programme, The Babraham Institute, Cambridge, UK. wolf.reik@babraham.ac.uk.
11
Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. wolf.reik@babraham.ac.uk.
12
Wellcome Sanger Institute, Hinxton, Cambridge, UK. wolf.reik@babraham.ac.uk.
13
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. thornton@ebi.ac.uk.

Abstract

BACKGROUND:

Epigenetic clocks are mathematical models that predict the biological age of an individual using DNA methylation data and have emerged in the last few years as the most accurate biomarkers of the aging process. However, little is known about the molecular mechanisms that control the rate of such clocks. Here, we have examined the human epigenetic clock in patients with a variety of developmental disorders, harboring mutations in proteins of the epigenetic machinery.

RESULTS:

Using the Horvath epigenetic clock, we perform an unbiased screen for epigenetic age acceleration in the blood of these patients. We demonstrate that loss-of-function mutations in the H3K36 histone methyltransferase NSD1, which cause Sotos syndrome, substantially accelerate epigenetic aging. Furthermore, we show that the normal aging process and Sotos syndrome share methylation changes and the genomic context in which they occur. Finally, we found that the Horvath clock CpG sites are characterized by a higher Shannon methylation entropy when compared with the rest of the genome, which is dramatically decreased in Sotos syndrome patients.

CONCLUSIONS:

These results suggest that the H3K36 methylation machinery is a key component of the epigenetic maintenance system in humans, which controls the rate of epigenetic aging, and this role seems to be conserved in model organisms. Our observations provide novel insights into the mechanisms behind the epigenetic aging clock and we expect will shed light on the different processes that erode the human epigenetic landscape during aging.

KEYWORDS:

Aging; Biological age; DNA methylation; Developmental disorder; Epigenetic clock; Epigenetics; H3K36 methylation; Methylation entropy; NSD1; Sotos syndrome

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center