Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity
Baars, Matthijs J.D.; Douma, Thera; Simeonov, Dimitre R.; Myers, Darienne R.; Kulhanek, Kayla; Banerjee, Saikat; Zwakenberg, Susan; Baltissen, Marijke P.; Amini, Mojtaba; de Roock, Sytze; van Wijk, Femke; Vermeulen, Michiel; Marson, Alexander; Roose, Jeroen P.; Vercoulen, Yvonne
(2021) European Journal of Immunology, volume 51, issue 2, pp. 471 - 482
(Article)
Abstract
RasGRP1 is a Ras guanine nucleotide exchange factor, and an essential regulator of lymphocyte receptor signaling. In mice, Rasgrp1 deletion results in defective T lymphocyte development. RASGRP1-deficient patients suffer from immune deficiency, and the RASGRP1 gene has been linked to autoimmunity. However, how RasGRP1 levels are regulated, and if RasGRP1
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dosage alterations contribute to autoimmunity remains unknown. 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. In patients with autoimmunity, active inflammation correlated with decreased RASGRP1 levels in CD4+ T cells. By analyzing H3K27 acetylation profiles in human T cells, we identified a RASGRP1 enhancer that harbors autoimmunity-associated SNPs. CRISPR-Cas9 disruption of this enhancer caused lower RasGRP1 expression, and decreased binding of RUNX1 and CBFB transcription factors. Analyzing patients with autoimmunity, we detected reduced RUNX1 expression in CD4+ T cells. 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.
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Keywords: autoimmunity, RASGRP1, RUNX1, T cells, transcription, Autoimmunity/genetics, Humans, Mice, Inbred C57BL, Guanine Nucleotide Exchange Factors/genetics, Core Binding Factor Alpha 2 Subunit/genetics, Mice, Knockout, CRISPR-Cas Systems/genetics, Animals, DNA-Binding Proteins/genetics, CD4-Positive T-Lymphocytes/immunology, Transcription, Genetic/genetics, Inflammation/genetics, Mice, Histones/genetics, Gene Expression Regulation/genetics, Immunology and Allergy, Immunology, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural
ISSN: 0014-2980
Publisher: Wiley-VCH Verlag
Note: Funding Information: The authors wish to thank Oghenekevwe Michelle Gbenedio, Flow Cytometry Core (NIH P30DK063720, UCSF), Marten Hornsveld (LUMC), Fried Zwartkruis, Jose Ramos-Pittol, Rina Wichers, Flow Cytometry Core (UMCU) for assistance. Funding was provided by NWO: Gravitation programme Cancer Genomics Center (024.001.028), and Marie-Sklodowska Curie PIOF-GA-2012-328666 (to YV), NSF-GRFP (1650113 to DRM) and NIH-NIAID (R01-AI104789 and P01-AI091580 to JPR), Jeffrey G. Klein Family Fellowship in Diabetes (DRS), NIH-NIAID (DP3DK111914-01 (NIDDK) and R01DK1199979 (NIDDK), to AM), the National Multiple Sclerosis Society (A.M.; grant no. CA 1074-A-21, Innovative Genomics Institute (IGI, to AM), the Northern California JDRF Center of Excellence (AM). A.M. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund and received the Lloyd Old STAR career award from the Cancer Research Institute. A.M. is an investigator at the Chan Zuckerberg Biohub and a member of the Parker Institute for Cancer Immunotherapy (PICI). The Vermeulen lab?is in the Oncode Institute, which is co-funded by the Dutch Cancer Society (KWF). Funding Information: Funding was provided by NWO: Gravitation programme Cancer Genomics Center (024.001.028), and Marie‐Sklodowska Curie PIOF‐GA‐2012‐328666 (to YV), NSF‐GRFP (1650113 to DRM) and NIH‐NIAID (R01‐AI104789 and P01‐AI091580 to JPR), Jeffrey G. Klein Family Fellowship in Diabetes (DRS), NIH‐NIAID (DP3DK111914‐01 (NIDDK) and R01DK1199979 (NIDDK), to AM), the National Multiple Sclerosis Society (A.M.; grant no. CA 1074‐A‐21, Innovative Genomics Institute (IGI, to AM), the Northern California JDRF Center of Excellence (AM). A.M. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund and received the Lloyd Old STAR career award from the Cancer Research Institute. A.M. is an investigator at the Chan Zuckerberg Biohub and a member of the Parker Institute for Cancer Immunotherapy (PICI). The Vermeulen lab is in the Oncode Institute, which is co‐funded by the Dutch Cancer Society (KWF). Publisher Copyright: © 2020 The Authors. European Journal of Immunology published by Wiley-VCH GmbH
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