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

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. Electronic supplementary material The online version of this article (10.1186/s13059-019-1753-9) contains supplementary material, which is available to authorized users.

MethylNet: an automated and modular deep learning approach for DNA methylation analysis

“…MethylNet methodology presents alternative framework to uncover functional gene regulation that accounts for biological age acceleration and goes beyond the limited set of features used to predict methylation age in Horvath, Hannum, and other DNA methylation clocks. As the biology of these clocks are still being discovered [41] and due to the non-linear relationship with both chronological age [42] and other biomarkers of cell epigenetic cell maturation [43], further examination of age acceleration and biology should be done through neural networks.…”

DNA Methylation in the Diagnosis of Monogenic Diseases

“…Significantly, blood SS epi-signatures allowed researchers to discriminate between pathogenic NSD1 mutations and benign NSD1 variants [30]. As part of their methylation defect, an acceleration of the Horvath's epigenetic aging clock was also demonstrated in SS patients [31].…”

New Targeted Approaches for Epigenetic Age Predictions

“…Epigenetic clocks raise hopes as a biomarker in forensic medicine, to determine donor age of an unknown specimen or of a person with allegedly unknown age (Horvath and Raj 2018). On the other hand, accelerated epigenetic aging has been shown to be associated with shorter life expectancy (Marioni et al 2015;Lin et al 2016;Zhang et al 2017;Lu et al 2019;Lund et al 2019), and it is liable to be affected by environmental exposure, gender, specific mutations and diseases (Fiorito et al 2019;Jeffries et al 2019;Martin-Herranz et al 2019). Therefore, epigenetic clocks seem to reflect aspects of biological age, which opens perspectives as a surrogate for intervention studies.…”