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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.

SUBMITTER: Martin-Herranz DE

PROVIDER: S-EPMC6693144 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Martin-Herranz Daniel E DE Aref-Eshghi Erfan E Bonder Marc Jan MJ Stubbs Thomas M TM Choufani Sanaa S Weksberg Rosanna R Stegle Oliver O Sadikovic Bekim B Reik Wolf W Thornton Janet M JM

Genome biology 20190814 1

<h4>Background</h4>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.<h4>Results ...[more]

PMID: 31409373

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Project description:Nuclear receptor-binding SET domain protein 1 (NSD1) prototype is a family of mammalian histone methyltransferases (NSD1, NSD2/MMSET/WHSC1, NSD3/WHSC1L1) that are essential in development and are mutated in human acute myeloid leukemia (AML), overgrowth syndromes, multiple myeloma and lung cancers. In AML, the recurring t(5;11)(q35;p15.5) translocation fuses NSD1 to nucleoporin-98 (NUP98). Here, we present the first characterization of the transforming properties and molecular mechanisms of NUP98-NSD1. We demonstrate that NUP98-NSD1 induces AML in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes. Mechanistically, NUP98-NSD1 binds genomic elements adjacent to HoxA7 and HoxA9, maintains histone H3 Lys 36 (H3K36) methylation and histone acetylation, and prevents EZH2-mediated transcriptional repression of the Hox-A locus during differentiation. Deletion of the NUP98 FG-repeat domain, or mutations in NSD1 that inactivate the H3K36 methyltransferase activity or that prevent binding of NUP98-NSD1 to the Hox-A locus precluded both Hox-A gene activation and myeloid progenitor immortalization. We propose that NUP98-NSD1 prevents EZH2-mediated repression of Hox-A locus genes by colocalizing H3K36 methylation and histone acetylation at regulatory DNA elements. This report is the first to link deregulated H3K36 methylation to tumorigenesis and to link NSD1 to transcriptional regulation of the Hox-A locus. Experiment Overall Design: Total RNA was extracted from stably transformed progenitors cultured in vitro and the expression levels of mRNA transcripts quantified using the Affymetrix GeneChip Mouse Genome 430 2.0 array, as previously described. The GEO database accession numbers: for progenitors immortalized by HoxA9 (GSM190542, GSM190546, GSM190547); for progenitors immortalized by coexpressed HoxA9 plus Meis1 (GSM190548, GSM190549, GSM190550); for progenitors immortalized by NUP98-NSD1 (GSM190551, GSM190552, GSM190553); and for progenitors immortalized by MLL-ENL (GSM190554). Experiment Overall Design: NOTE: CEL files and dChip data were requested by GEO but not provided.

Project description:ImportanceNeighborhood deprivation is associated with age-related disease, mortality, and reduced life expectancy. However, biological pathways underlying these associations are not well understood.ObjectiveTo evaluate the association between neighborhood deprivation and epigenetic measures of age acceleration and genome-wide methylation.Design, setting, and participantsThis cross-sectional study used data from the Sister Study, a prospective cohort study comprising 50 884 women living in the US and Puerto Rico aged 35 to 74 years at enrollment who had a sister with breast cancer but had not had breast cancer themselves. Cohort enrollment occurred between July 2003 and March 2009. Participants completed a computer-assisted telephone interview on demographic, socioeconomic, lifestyle, and residential factors and provided anthropometric measures and peripheral blood samples at a home examination. DNA methylation data obtained for 2630 non-Hispanic White women selected for a case-cohort study in 2014 were used in this cross-sectional analysis. DNA methylation was measured using the HumanMethylation450 BeadChips in whole blood samples collected at baseline. Data analysis for this study was performed from October 17, 2019, to August 27, 2020.ExposuresEach participants' primary address was linked to an established index of neighborhood deprivation.Main outcomes and measuresEpigenetic age was estimated using 4 epigenetic clocks (Horvath, Hannum, PhenoAge, and GrimAge). Age acceleration was determined using residuals from regressing chronologic age on each of the 4 epigenetic age metrics. Linear regression was used to estimate associations between neighborhood deprivation and epigenetic age acceleration as well as DNA methylation at individual cytosine-guanine sites across the genome.ResultsMean (SD) age of the 2630 participants was 56.9 (8.7) years. Those with the greatest (>75th percentile) vs least (≤25th percentile) neighborhood deprivation had higher epigenetic age acceleration estimated by Hannum (β = 0.23; 95% CI, 0.01-0.45), PhenoAge (β = 0.28; 95% CI, 0.06-.50), and GrimAge (β = 0.37; 95% CI, 0.12-0.62). Increasing US quartiles of neighborhood deprivation exhibited a trend with Hannum, PhenoAge, and GrimAge. For example, GrimAge showed a significant dose-response (P test for trend <.001) as follows: level 2 vs level 1 (β = 0.30; 95% CI, 0.17-0.42), level 3 vs level 1 (β = 0.35; 95% CI, 0.19-0.50), and level 4 vs level 1 (β = 0.37; 95% CI, 0.12-0.62). Neighborhood deprivation was found to be associated with 3 cytosine-phosphate-guanine sites, with 1 of these annotated to a known gene MAOB (P = 9.71 × 10-08).Conclusions and relevanceThe findings of this study suggest that residing in a neighborhood with a higher deprivation index appears to be reflected by methylation-based markers of aging.

Dataset Information

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

Publications

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

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