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

epigenetic aging dna methylation tatton-brown-rahman syndrome dnmt3a cancer

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#1 Engadin

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Posted 08 June 2019 - 09:53 PM


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 DNMT3Avariants. 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.

 

 

Introduction

 

DNA methylation is an essential epigenetic process involving the addition of a methyl group to cytosine. It is known to play a role in many important genomic regulatory processes, including X-chromosome inactivation, genomic imprinting and the repression of tumor suppressor genes in cancer, mediating transcriptional regulation as well as genomic stability (Jones 2012). Three catalytically active DNA methyltransferases (DNMTs) are involved in the methylation of cytosine: DNMT1, which is mainly responsible for the maintenance of DNA methylation over replication and DNMT3A and DNMT3B, which generally perform de novo methylation of either unmethylated or hemimethylated DNA. An absence of these enzymes in mice results in embryonic (DNMT1 and 3B) or postnatal (DNMT3A) lethality (Okano et al. 1999), confirming their essential roles in development. In line with knockout mouse models, pathogenic variants affecting the chromatin binding domains of DNMT1 have been shown to cause two separate progressive autosomal dominant adult-onset neurologic disorders (Klein et al. 2011). Biallelic pathogenic variants in DNMT3B have been associated with immunodeficiency, centromere instability and facial anomalies (ICF) syndrome (Jiang et al. 2005). To date, DNMT3A has been linked to a number of physiological functions, including cellular differentiation, malignant disease, cardiac disease, learning and memory formation. Somatically acquired pathogenic variants in DNMT3A are associated with over 20% of acute myeloid leukemia (AML) cases, whilst heterozygous germline pathogenic variants have more recently been found to underlie Tatton-Brown-Rahman syndrome (TBRS; also known as DNMT3A-overgrowth syndrome, OMIM: 615879) (Challen et al. 2011Tatton-Brown et al. 2014). TBRS is characterized by increased growth, intellectual disability (ID) and dysmorphic facial features.

 

There is an emerging group of epigenetic regulatory molecule-associated human growth disorders where the underlying molecular defect is a disruption to the DNA methylation and histone machinery. There are now over 40 disorders identified within this group, which can be further subgrouped into diseases resulting from disruption of the ‘writers’, ‘readers’ and ‘erasers’ of epigenetic modifications (Bjornsson 2015). Example disorders in each group include Kabuki, Sotos and Weaver syndromes (‘writers’), Smith-Magenis, Rett and Bohring-Optiz syndromes (‘readers’), and Wilson-Turner and Cleas-Hensen syndromes (‘erasers’). The final subgroup occurs due to disruption of chromatin remodellers, with example resulting disorders including CHARGE and Floating Harbour syndromes. Neurological and cognitive impairment are common features of these conditions, suggesting that precise epigenetic regulation may be critical for neuronal homeostasis. However, a true understanding of the pathogenic mechanism underlying these conditions remains poorly understood.

 

In the current study, we investigated the methylomic consequences of a DNMT3Apathogenic variant (NC_000002.12:g.25240312C>T; NM_022552.4:c.2312G>A; p.Arg771Gln) in a large Amish family comprising four individuals affected with TBRS arising due to a mosaic pathogenic DNMT3A variant in their father (Xin et al. 2017). The occurrence of multiple affected and unaffected individuals in the same sibship, together with the combined genetic and environmental homogeneity of the Amish, permitted an in-depth investigation of the genome-wide patterns of DNA methylation associated with pathogenic variation in DNMT3A. We subsequently extended our analyses to other (non-Amish) TBRS patients harbouring distinct pathogenic de novo DNMT3A variants, as well other methyltransferase associated overgrowth and growth deficiency syndromes, defining altered epigenetic profiles as common key themes of these growth disorders.

 

 

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F U L L   T E X T :   bioRXiv

 







Also tagged with one or more of these keywords: epigenetic aging, dna methylation, tatton-brown-rahman syndrome, dnmt3a, cancer

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