Objective Systemic Lupus Erythematosus (SLE) displays a striking female predominance of almost 10:1. Unbiased analysis of our whole blood transcriptomic data from SLE patients unraveled SMC1A, a cohesin complex member, as a strong female-biased gene in SLE.¹ Our aim was to delineate the role of SMC1A in inflammation and sexual dimorphism of SLE.

Methods We assayed by RT-PCR and immunoblotting the SMC1A expression in blood-derived immune cell types of male/female SLE patients and healthy controls. We performed chromatin immunoprecipitation with next generation sequencing (ChIP-seq) to map the genome-wide regions of active transcription (H₃K₂₇ac) and SMC1A binding in monocytes cultured under basal and lupus-inducing conditions. Integrative analysis with public epigenomic and our transcriptomic data was conducted to define the genome regulatory role of SMC1A and specify putative target-genes upon lupus-like inflammation. ChIP-PCR was performed in male/female lupus-like monocytes to explore potential gender difference on SMC1A binding at gene regulatory regions. SMC1A silencing was used to confirm the regulatory role of SMC1A in specific target-genes. Finally, we compared the transcriptome profile of male/female SLE monocytes by Quant-seq.

Results SMC1A displays enhanced female-biased expression both in SLE patient monocytes and in cultured lupus-like monocytes. Upon lupus-like inflammation, SMC1A was repositioned preferentially at inflammatory enhancer regions which displayed increased chromatin accessibility and H₃K₂₇ac signal (indicative of open chromatin and active transcription, respectively). The enhanced SMC1A binding at active inflammatory enhancers was combined with transcriptional activation of the corresponding genes (n=212), suggesting the regulatory role of SMC1A in the transcription of major inflammatory genes. Additionally, SMC1A-silenced monocytes exhibited decreased production of SLE-associated inflammatory molecules (i.e., IL-6 and IL1-A) upon lupus-like inflammation. Importantly, IL-6 and IL-A displayed female-biased expression as well as female-biased SMC1A binding at the corresponding enhancers in lupus-like monocytes. Moreover, a substantial proportion of the SMC1A-regulated genes (92 out of 212) associated with activation of inflammatory response were found to be significantly overexpressed in female versus male SLE monocytes.

Conclusions This study highlights the role of SMC1A as a female-biased gene which regulates key autoimmune-related molecular pathways upon lupus-like inflammation, linking SMC1A with female predominance in SLE.

Reference

1. Panousis NI, et al. Ann Rheum Dis. 2019 Aug;78(8):1079–1089.

Acknowledgements This research is co-financed by: 1. Greece and the European Union (European Social Fund- ESF) through the Operational Programme «Human Resources Development, Education and Lifelong Learning» in the context of the project ‘Strengthening Human Resources Research Potential via Doctorate Research’ (MIS-5000432), implemented by the State Scholarships Foundation (ιΚΥ). 2. Hellenic Foundation for Research and Innovation (HFRI).