Study Of Chromatin Accessibility Associated With Type Ⅰ Interferon Signaling Pathway In Systemic Lupus Erythematosus

Objective: Our study focused on chromatin accessibility during type I interferon signaling pathway which closely related to systemic lupus erythematosus(SLE).In this way,we aim to provide new ideas and clues for classification diagnosis and targeted therapy of SLE diseases.Methods: At first,the ATAC-seq technique was used to identify the changed open chromatin regions where response to type I interferon in human monocytes.Next,ATAC-seq was continuously applied to identify the altered open chromatin regions after pretreatment with BRD4 inhibitor(+)-JQ1 before type I interferon treatment.Furthermore,RNA-seq and ATAC-seq data were combined to clarify the relationship between transcriptome and chromatin accessibility.At last,Real-time RTPCR was performed to detect the correlation between BRD4 and abnormally activated type I interferon signaling pathway in SLE patients,and ATAC-seq was used to measure aberrant open chromatin of type I interferon signaling in SLE patients and the effects of(+)-JQ1 inhibition.Realtime RT-PCR was used to varify these results from gene expression level.Results: We found the chromatin structure became more accessible at the loci of ISGs,especially effective ISGs,after treatment of type I interferon in human monocytes.Next,we found the regions that were up-regulated by interferon stimulation can be selectively down-regulated by BRD4 inhibitor(+)-JQ1.Furthermore,we demonstrated the data of ATAC-seq and RNA-seq had a good correlation.At last,we detected the expression of BRD4 in SLE patients and results showed a positive correlation with interferon scores.Both the abnormally activated open chromatin structure and ISG expression with type I interferon in SLE patients were restored by(+)-JQ1.Conclusion: After stimulated by type I interferon,the chromatin accessibility increased at the regions related to ISGs in human monocytes.(+)-JQ1 can inhibited interferon-activated open chromatin and reduce the expression of downstream ISGs.Meanwhile(+)-JQ1 also can repress abnormally activated open chromatin structure and the expression of ISG associated with type I interferon in SLE patients.