Abstract
People with ataxia-telangiectasia (A-T) display phenotypic variability with regard to progression of immunodeficiency, sino-pulmonary disease, and neurologic decline. To determine the association between differential gene expression, epigenetic state, and phenotypic variation among people with A-T, we performed transcriptional and genome-wide DNA methylation profiling in patients with mild and classic A-T progression as well as healthy controls. RNA and genomic DNA were isolated from peripheral blood mononuclear cells for transcriptional and DNA methylation profiling with RNA-sequencing and modified reduced representation bisulfite sequencing, respectively. We identified 555 genes that were differentially expressed among the control, mild A-T, and classic A-T groups. Genome-wide DNA methylation profiling revealed differential promoter methylation in cis with 146 of these differentially expressed genes. Functional enrichment analysis identified significant enrichment in immune, growth, and apoptotic pathways among the methylation-regulated genes. Regardless of clinical phenotype, all A-T participants exhibited downregulation of critical genes involved in B cell function (PAX5, CD79A, CD22, and FCRL1) and upregulation of several genes associated with senescence and malignancy, including SERPINE1. These findings indicate that gene expression differences may be associated with phenotypic variability and suggest that DNA methylation regulates expression of critical immune response genes in people with A-T.
| Original language | English (US) |
|---|---|
| Article number | 7479 |
| Journal | Scientific reports |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2020 |
Funding
SAM-M was supported by The A-T Children’s Project and NIH/NHLBI grant R01HL114800. PAR was supported by NIH/NHLBI K08HL146943, the Parker B. Francis Fellowship, and the ATS Foundation/Boehringer Ingelheim Pharmaceuticals Inc. Research Fellowship in IPF. BDS was supported by NIH/NHLBI grants K08HL128867 and R01HL149883. The content of this publication does not necessarily reflect the views or polices of the Department of Health and Human Services, Francis Family Foundation, or the American Thoracic Society. This research was supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster, which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Feinberg’s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. The Genomics Compute Cluster is part of Quest, Northwestern University’s high performance computing facility, with the purpose to advance research in genomics.
ASJC Scopus subject areas
- General