The X-linked chromatin modifier SMC1A is deregulated in lupus female monocytes and promotes autoimmunity [RNA-Seq]

Biological sex underlines the onset of autoimmunity yet the underlying molecular mechanisms remain ill-defined. Female susceptibility is prominent in systemic lupus erythematosus (SLE), an autoimmune disease of substantial burden. Herein we demonstrate that SMC1A, a subunit of the cohesin complex that escapes X-chromosome inactivation, exhibits female-biased expression in monocytes from SLE patients and those cultured under lupus-inducing stimulus. By altering SMC1A dosage, the expression of immune-related genes, particularly those responsive to lupus environment, was affected. Active enhancers of immune and inflammatory pathways showed widespread SMC1A redistribution in lupus-like monocytes, as revealed by integrated analysis of SMC1A binding, chromatin activity and accessibility. Our data support SMC1A as a sex-biased chromatin modifier that enhances inflammatory responses in lupus. Overall design: RNA-seq data from peripheral blood of 15 individuals in each of four groups -healthy male, healthy female and SLE male, SLE female- was analyzed to identify sexually differential gene expression in SLE patients compared to healthy controls. Some of these samples were previously published, with 20 of the total samples being analyzed for the first time in this study. To investigate the role of SMC1A in gene transcription regulation in human monocytes during lupus-like inflammation, we silenced SMC1A in CD14+ monocytes isolated from blood of three healthy donors. The cells were treated with IFNa and TNF for 18h and LPS for 3h and RNA-seq was perfromed on cells from the following conditions: si_control unstimulated, si_control IFNa TNF LPS stimulated, si_smc1a unstimulated, si_smc1a IFNa TNF LPS stimulated. Focusing on the whole blood-derived monocytes, we analyzed the transciptomic differences between monocytes from healthy donors and SLE patients by conducting RNA-seq on CD14+ monocytes isolated form the blood of 5 healthy donors and 6 SLE patients. To delineate the sexually differential expressed genes in SLE monocytes, blood CD14+ monocytes were isolated from 10 male and 8 female patients with SLE, cultured with 10 ng/ml MCSF for 18 h and QuantSeq 3' mRNA sequencing was performed