Background Bennett et al identified the presence of interferon gene expression signatures in peripheral blood of children with systemic lupus erythematosus (pSLE). Here, we aim to identify how B cells contribute to those signatures. We hypothesize that disordered transcription in pSLE will be prominent in B cells and attributed to disease-specific epigenetic alterations. Thus we will not only identify important disease mechanisms in SLE, we will shed light on the genetics of SLE. Our previously published work demonstrated that most of the genetic risk for SLE located within non-coding regions of the genome appears to also contain higher than baseline epigenetic modifications of DNA and transcription factor binding sites that regulate and coordinate transcription.
Methods Our specific aim is to assess regions of open chromatin in untreated pSLE and compare findings with healthy children. We propose to use assays of transposase-accessible chromatin with sequencing (ATACseq) to broadly survey open regions of chromatin and clarify the functional epigenome. In this pilot study, we propose to determine feasibility of performing this assay and developing methods for data analysis using 5 pediatric lupus patients and 5 healthy children.
Anticipated results and conclusions Our long-term goal is to gain a mechanistic understanding of the aberrant transcriptional signatures in untreated SLE. The data generated by this pilot study will provide the basis for a rigorous power analysis, and firmly establish the working relationship between the Buffalo and Cohen Children’s Medical Center groups, both of which will be essential for a competitive application to NIH. Our preliminary findings from this pilot study will also allow us to begin the exciting process of linking the genetics and epigenetics of pSLE to the well-established transcriptional aberration.
Acknowledgements This study is funded, in part, by an Arthritis Foundation-Childhood Arthritis and Rheumatology Research Alliance Small Pilot Grant.
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