We have edited the figure legends and figures following the EJI standards. Upon editorial request, we have moved Figures 1B-E to the supplements (now, Figure 1- supplement A-E). All changes in the text are marked, and all changed figures/novel figures are noted below in our response. We have performed additional experiments, and revised the manuscript as well as the figures to address the reviewer’s and editorial requests. Please find below our response to all points raised by reviewers. The authors would like to thank the reviewers and editor for their efforts and suggestions that have allowed us to improve our manuscript. Title: "Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity" We look forward to hearing from you and thank you for submitting your manuscript to the European Journal of Immunology. You should therefore check that all the information (including author names) is correct as changes will NOT be permitted until the proofs stage. The files used for the Accepted Articles are the final files and information supplied by you in Manuscript Central. Please note that EJI articles are now published online a few days after final acceptance (see Accepted Articles: ). For final acceptance, please follow the instructions below and return the requested items as soon as possible as we cannot process your manuscript further until all items listed below are dealt with. It is a pleasure to provisionally accept your manuscript entitled "Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity" for publication in the European Journal of Immunology. Lastly, we mechanistically link RUNX1 to transcriptional regulation of RASGRP1 to reveal a key circuit regulating RasGRP1 expression, which is vital to prevent inflammatory disease. Analyzing patients with autoimmunity, we detected reduced RUNX1 expression in CD4(+) T cells. CRISPR-Cas9 disruption of this enhancer caused lower RasGRP1 expression, and decreased binding of RUNX1 and CBFB transcription factors. By analyzing H3K27 acetylation profiles in human T cells, we identified a RASGRP1 enhancer that harbors autoimmunity-associated SNPs. In patients with autoimmunity, active inflammation correlated with decreased RASGRP1 levels in CD4(+) T cells. We demonstrate that diminished Rasgrp1 expression caused defective T lymphocyte selection in C57BL/6 mice, and that the severity of inflammatory disease inversely correlates with Rasgrp1 expression levels. However, how RasGRP1 levels are regulated, and if RasGRP1 dosage alterations contribute to autoimmunity remains unknown. RASGRP1-deficient patients suffer from immune deficiency, and the RASGRP1 gene has been linked to autoimmunity. In mice, Rasgrp1 deletion results in defective T lymphocyte development. RasGRP1 is a Ras guanine nucleotide exchange factor, and an essential regulator of lymphocyte receptor signaling.
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