Abstract
AbstractHNRNPU encodes a multifunctional RNA-binding protein that plays critical roles in regulating pre-mRNA splicing, mRNA stability, and translation. Aberrant expression and dysregulation of HNRNPU have been implicated in various human diseases, including cancers and neurological disorders. We applied a next generation sequencing based assay (EPIC-NGS) to investigate genome-wide methylation profiling for >2 M CpGs for 7 individuals with a neurodevelopmental disorder associated with HNRNPU germline pathogenic loss-of-function variants. Compared to healthy individuals, 227 HNRNPU-associated differentially methylated positions were detected. Both hyper- and hypomethylation alterations were identified but the former predominated. The identification of a methylation episignature for HNRNPU-associated neurodevelopmental disorder (NDD) implicates HNPRNPU-related chromatin alterations in the aetiopathogenesis of this disorder and suggests that episignature profiling should have clinical utility as a predictor for the pathogenicity of HNRNPU variants of uncertain significance. The detection of a methylation episignaure for HNRNPU-associated NDD is consistent with a recent report of a methylation episignature for HNRNPK-associated NDD.
Funder
RCUK | Medical Research Council
DH | National Institute for Health Research
Rosetrees Trust
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics
Reference36 articles.
1. Sadikovic B, Levy MA, Kerkhof J, Aref-Eshghi E, Schenkel L, Stuart A, et al. Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders. Genet Med. 2021;23:1065–74.
2. Levy MA, McConkey H, Kerkhof J, Barat-Houari M, Bargiacchi S, Biamino E, et al. Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders. HGG Adv. 2022;3:100075.
3. Romig H, Fackelmayer FO, Renz A, Ramsperger U, Richter A. Characterization of SAF-A, a novel nuclear DNA binding protein from HeLa cells with high affinity for nuclear matrix/scaffold attachment DNA elements. EMBO J. 1992;11:3431–40.
4. Wu B, Su S, Patil DP, Liu H, Gan J, Jaffrey SR, et al. Molecular basis for the specific and multivariant recognitions of RNA substrates by human hnRNP A2/B1. Nat Commun. 2018;9:420.
5. Gillentine MA, Wang T, Hoekzema K, Rosenfeld J, Liu P, Guo H, et al. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders. Genome Med. 2021;13:63.
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献