Investigating the DNA Methylation Episignature for the Epilepsy Gene CHD2
Abstract number :
1.368
Submission category :
12. Genetics / 12A. Human Studies
Year :
2023
Submission ID :
440
Source :
www.aesnet.org
Presentation date :
12/2/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Helen Pennington, Undergraduate Student – St. Jude Children's Research Hospital
Christy LaFlamme, MS – St. Jude Children's Research Hospital; Cassandra Rastin, MSc – University of Western Ontario; Lynette Sadleir, MD – University of Otago; Ingrid Scheffer, PhD – The University of Melbourne; Bekim Sadikovic, PhD – University of Western Ontario; Heather Mefford, MD, PhD – St. Jude Children's Research Hospital
Rationale:
Pathogenic, loss of function (LOF) variants in the chromatin remodeler CHD2 cause developmental and epileptic encephalopathy (DEE). Affected individuals also harbor a unique peripheral blood-derived DNA methylation signature or “episignature.” Episignatures consist of distinct sets of CpG probes across the genome, the methylation status of which can now distinguish over 100 different genetic disorders and syndromes. Episignatures have been shown to have high clinical utility for diagnosis, but many questions remain about how they can potentially inform basic biological and disease mechanisms.
Methods:
Here, we investigate the exceptionally robust episignature for the DEE gene CHD2 using CHD2 blood-derived DNA samples for the Infinium MethylationEPIC 850K array (n=18 samples) and whole genome bisulfite sequencing (WGBS; n=3 trios and 2 singletons). We first redefine the CHD2 episignature on the more recent 850K array and compare it to the currently reported 450K array episignature. Next, we identify differentially methylated regions (DMRs) between individuals with CHD2 variants and controls in the EpiSign Knowledge Database using the 850K array. We use WGBS data to assess DNA methylation at approximately 23 million CpGs across the genome, allowing us to more accurately define the CHD2-related DMRs and perform additional functional genomic annotation.
Results:
We find that a subset of CHD2 episignature probes overlaps with CHD2 DMRs, connecting the episignature to potential genome regulation. We validate CHD2 DMRs called from the array with WGBS and show that higher resolution afforded by WGBS better resolves DMRs and provides additional information about how CHD2 LOF differentially regulates DNA methylation more broadly.
Conclusions:
Here, we functionally characterize the episignature for CHD2 thereby highlighting the utility of episignatures to give insights into underlying biology. Importantly, in-depth examination of the CHD2 episignature informs potential disease mechanisms and warrants future investigations of DMRs in brain-relevant cell types to study how episignatures may impact gene expression. This research serves as the first, essential step toward fully understanding the CHD2 episignature and supports the notion that DNA methylation could potentially serve as a biomarker toward CHD2 therapeutic development.
Funding: Rhodes College Summer Plus Fellowship. CURE.
Genetics