Ets1 Controls the Development of B Cell Autoimmune Responses in a Cell-Intrinsic Manner

Abstract

Ets1 is emerging as a key transcription factor that is required to prevent autoimmunity in mice and humans. Ets1 is expressed in both B and T cells, and mice lacking Ets1 are characterized by excess B and T cell activation, leading to enhanced formation of Ab-secreting cells and high titers of autoantibodies. In humans, genome-wide association studies have detected associations of single nucleotide polymorphisms in the human ETS1 gene with autoimmune diseases, including lupus. An increased fraction of CD4 + T cells from Ets1 2/2 mice have an activated effector-memory phenotype, and there are aberrations in differentiation that contribute to the autoimmune phenotype. In vitro studies of B cells suggest that Ets1 may have B cell-intrinsic effects as well. To confirm B cell-intrinsic roles for Ets1, we crossed CD19-Cre mice to mice with a floxed allele of Ets1. Mice with a B cell-specific deletion of Ets1 show increases in B cell activation, numbers of Ab-secreting cells, and levels of autoantibodies, despite the fact that T cells are normal. However, when compared with conventional Ets1 knockout mice, mice with B cell-specific loss of Ets1 have a significantly milder phenotype. These results demonstrate that Ets1 is required in B cells to prevent autoimmune responses but that loss of Ets1 activity in other cell types is required for maximal autoimmune phenotypes. ImmunoHorizons, 2019, 3: 331-340.

Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming

“…They also reflected TFBS patterns that favoured proliferative responses. Namely, B cell CpG enrichment inferred increased binding of EZH2, which is increased in cell proliferation and lymphoma31 and reduced binding of (1) GATA3, suggesting increased cell proliferation32, (2) ETS1 which is required to prevent autoimmune responses33 and (3) NFATC2, involved in anergy, which, when reduced, causes a hyperproliferative phenotype 34. In T cells, there was inferred reduction in p300 binding, which would impair Foxp3 + T-regulatory cell function35; and enrichment of HIF1-α, which promotes Th17 differentiation and reduced Foxp3 + expression 36.…”

Combinatorial ETS1-Dependent Control of Oncogenic NOTCH1 Enhancers in T-cell Leukemia

“…It is worth noting that outside the T-cell compartment Ets1 plays a role in the maturation of other hematopoietic cells, such as B cells (31,39,42,(51)(52)(53)(54)(55)(56)(57)(58)(59). Thus, even though the effects of Ets1 on thymopoiesis are cell autonomous (17,18) and B cells are dispensable for early T-cell development, it cannot be ruled out that some effect of Ets1 inactivation in non-T-cell hematopoietic populations could influence the thymic phenotypes described here.…”

Single cell atlas for 11 non-model mammals, reptiles and birds

“…6a and Supplementary Data 16 ). Encouragingly, several regulators for AT1 cells (Cux1 and Gata6) 63 , AT2 cells (Etv5) 63 , ciliated cells (Rfx3 and Glis3) 64 , 65 , secretory cells (Nfib) 66 , fibroblasts (Zeb2 and Foxp1) 67 , 68 , endothelial cells (Tcf12 and Dach1) 69 , 70 , macrophages (Mef2a and PPARg) 71 , 72 , T cells (Sox5 and Ikzf1) 73 , 74 , and B cells (Mef2c and Ets1) 75 , 76 were active in the genetic regulatory network of the corresponding cell types (Supplementary Data 16 ), consistent with their expected regulatory functions. Of particular interest, we found a variety of regulatory circuits that were highly conserved among multiple species.…”