Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging

Abstract

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3A (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G>A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated to genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. Notably, these findings were most striking in a carrier of the AML associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders; NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamentally new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance and determinants of biological aging in these growth disorders.

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

“…A recent preprint has shown that loss-of-function mutations in DNMT3A, which cause Tatton-Brown-Rahman overgrowth syndrome, also lead to a higher ticking rate of the epigenetic ageing clock [64]. They also report positive epigenetic age acceleration in Sotos syndrome and negative acceleration in Kabuki syndrome, consistent with our results.…”

“…They also report positive epigenetic age acceleration in Sotos syndrome and negative acceleration in Kabuki syndrome, consistent with our results. Furthermore, they observe a DNA methylation signature in the DNMT3A mutants characterised by widespread hypomethylation, with a modest enrichment of DMPs in regions upstream of the transcription start site, shores and enhancers [64], which we also detect in our 'Hypo-Hypo DMPs' (those that become hypomethylated both during physiological ageing and in Sotos). Therefore, the hypomethylation observed in our 'Hypo-Hypo DMPs' is consistent with a reduced methylation activity of DNMT3A, which in our system could be a consequence of the decreased recruitment of DNMT3A to genomic regions that have lost H3K36 methylation (Fig.…”

Epigenetic age is accelerated in schizophrenia with age- and sex-specific effects and associated with polygenic disease risk

“…We did not observe age deceleration in postmortem brain samples of the human cortex, indicating the the observe signal may be blood-specific. Horvath DNAm aging has been shown to associate with molecular processes of development and cell differentiation 12,32 , including human (neuro)developmental phenotypes 45,46 . Our findings may indicate that individuals diagnosed with SCZ in this age group show evidence of delayed or deficient development and that this is detectable in blood through the multi-tissue Horvath clock.…”

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.…”