Background The dysregulation of enhancers has been observed in many autoimmune diseases, but it is still a big challenge to identify the function, the target genes, and the pathogenic roles of the dysregulated enhancers. Here, we intend to dissect the enhancer regulatory landscape of a SLE critical microRNA in different cell lineages and identify the SLE-associated enhancers, which would be intervened by CRISPR as possible therapeutic targets.

Methods Epigenomic analysis and 4C-seq study were carried out to identify candidate enhancers of miR-146a. CRISPR-dCas9-VP64 mediated activation was adopted to map the functional enhancers. The chromatin accessibility of different immune cell subpopulations from the healthy control and SLE patients was analyzed to identify SLE-dysregulated enhancer. The transcription factor binding was analyzed to dissect the mechanism that mediates enhancer dysfunction. The SLE-associated enhancer was targeted to intervene in the disease phenotype in SLE patients‘ PBMCs through CRISPR activation approach.

Results The cell-type-specific and shared enhancers of miR-146a were identified in different cell lineages. An enhancer, 32.5 kb away from the downstream of miR-146a, is dysregulated in SLE, with lower chromatin accessibility than the healthy control. The chromatin openness of this enhancers was positively correlated with the miR-146a expression and negatively correlated with SLEDAI scores of SLE patients. Moreover, the decreased expression of CEBPA mediated the dysregulation of this enhancer. Furthermore, CRISPR-based activation targeting this enhancer attenuated ISGs expression in SLE patients’ PBMCs.

Conclusions We developed an integrative approach to establish the enhancer landscape of the SLE critical gene, and dissect the mechanism that mediates the enhancer dysfunction in SLE. Our work reveals a possible therapeutical target for SLE treatment.