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Ets1 and IL17RA cooperate to regulate autoimmune responses as well as skin immunity to Staphylococcus aureus

ABSTRACT: Autoimmune diseases display many changes to the immune environment. The lineage-specific transcription factor Ets1 has been associated with autoimmune diseases including SLE. Ets1KO mice develop significant autoimmune disease with an expansion of IL-17 expressing lymphocytes. To ascertain the role of IL-17 in the phenotype of Ets1KO mice, mice lacking both Ets1 and IL17Ra were generated. These double-knockout mice (DKO) were found to develop significant autoimmune disease characterized by development of spontaneous skin lesions. To ascertain the potential causative factors contributing to the lesional skin development, RNA sequencing was conducted on ventral neck skin bulk RNA samples harvested from wild-type, Ets1KO, IL17RaKO, and DKO animals. We report here that Ets1 and IL17Ra deletion results in significant gene expression changes. Among the changes in gene expression reported here is significantly elevated expression of proinflammatory cytokines commonly part of the normal skin immune response to wounding and/or infection. Together these data suggest that Ets1 and Il17Ra signaling interact resulting in significantly altered immune related gene expression in the skin of DKO mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE237696 | GEO | 2023/09/13

REPOSITORIES: GEO

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Project description:The levels of transcription factor Ets1 are high in resting B and T cells, but are downregulated by signaling through antigen receptors and Toll-like receptors (TLRs). Loss of Ets1 in mice leads to excessive immune cell activation and development of an autoimmune syndrome and reduced Ets1 expression has been observed in human PBMCs in the context of autoimmune diseases. In B cells, Ets1 serves to prevent premature activation and differentiation to antibody-secreting cells. Given these important roles for Ets1 in the immune response, stringent control of Ets1 gene expression levels is required for homeostasis. However, the genetic regulatory elements that control expression of the Ets1 gene remain relatively unknown. Here we identify a topologically-associating domain (TAD) in the chromatin of B cells that includes the mouse Ets1 gene locus and describe an interaction hub that extends over 100 kb upstream and into the gene body. Additionally, we compile epigenetic datasets to find several putative regulatory elements within the interaction hub by identifying regions of high DNA accessibility and enrichment of active enhancer histone marks. Using reporter constructs, we determine that DNA sequences within this interaction hub are sufficient to direct reporter gene expression in lymphoid tissues of transgenic mice. Further analysis indicates that the reporter construct drives faithful expression of the reporter gene in mouse B cells, but variegated expression in T cells, suggesting the existence of T cell regulatory elements outside this region. To investigate how the downregulation of Ets1 transcription is associated with alterations in the epigenetic landscape of stimulated B cells, we performed ATAC-seq in resting and BCR-stimulated primary B cells and identified four regions within and upstream of the Ets1 locus that undergo changes in chromatin accessibility that correlate to Ets1 gene expression. Interestingly, functional analysis of several putative Ets1 regulatory elements using luciferase constructs suggested a high level of functional redundancy. Taken together our studies reveal a complex network of regulatory elements and transcription factors that coordinate the B cell-specific expression of Ets1.

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Ets1 and IL17RA cooperate to regulate autoimmune responses as well as skin immunity to Staphylococcus aureus

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