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.
Highlights
People with ataxia-telangiectasia (A-T) display phenotypic variability with regard to progression of immunodeficiency, sino-pulmonary disease, and neurologic decline
Following grouping of study participants, isolated peripheral blood mononuclear cells (PBMCs) enriched for lymphocytes were used for genome-wide transcriptional and DNA methylation profiling studies with RNA-sequencing (RNA-seq) and modified reduced representation bisulfite sequencing, respectively
We found that variability in A-T phenotype correlated with changes in gene expression and epigenetic signature
Summary
People with ataxia-telangiectasia (A-T) display phenotypic variability with regard to progression of immunodeficiency, sino-pulmonary disease, and neurologic decline. 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. A subset of individuals with A-T exhibit functionally normal immune function with milder and slower neurological progression[10] Despite this contrast in immune profile, individuals with this mild (atypical) A-T phenotype have a higher risk for cancer, similar to the risk for individuals with classic A-T. Having these tools could help with disease surveillance and improve survival for people with A-T
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