Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity,European Journal of Immunology

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Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity
European Journal of Immunology ( IF 4.5 ) Pub Date : 2020-10-16 , DOI: 10.1002/eji.201948451
Matthijs J D Baars ₁ , Thera Douma ₂ , Dimitre R Simeonov _{3,

4} , Darienne R Myers _{4,

5} , Kayla Kulhanek ₅ , Saikat Banerjee ₅ , Susan Zwakenberg ₁ , Marijke P Baltissen ₆ , Mojtaba Amini ₁ , Sytze de Roock ₇ , Femke van Wijk _{2,

7} , Michiel Vermeulen ₆ , Alexander Marson _{3,

8,

9,

10} , Jeroen P Roose ₅ , Yvonne Vercoulen ₁

Affiliation

Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Center of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Diabetes Center, University of California San Francisco, San Francisco, CA, USA.
Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA.
Department of Anatomy, University of California San Francisco, San Francisco, CA, USA.
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, Nijmegen, The Netherlands.
Pediatric Immunology and Rheumatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
J. David Gladstone Institutes, San Francisco, CA, USA.
Department of Medicine, University of California, San Francisco, CA, USA.
Department of Microbiology and Immunology, University of California, San Francisco, CA, USA.

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 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.

中文翻译：

通过 RUNX1 介导的转录失调的 RASGRP1 表达可促进自身免疫

RasGRP1 是一种 Ras 鸟嘌呤核苷酸交换因子，也是淋巴细胞受体信号传导的重要调节因子。在小鼠中， Rasgrp1缺失会导致 T 淋巴细胞发育缺陷。 RASGRP1缺陷的患者患有免疫缺陷，并且RASGRP1基因与自身免疫有关。然而，RasGRP1 水平是如何调节的，以及 RasGRP1 剂量的改变是否会导致自身免疫仍不清楚。我们证明 Rasgrp1 表达减少导致 C57BL/6 小鼠 T 淋巴细胞选择缺陷，并且炎症性疾病的严重程度与 Rasgrp1 表达水平呈负相关。在患有自身免疫性疾病的患者中，活动性炎症与 CD4 ⁺ T 细胞中RASGRP1水平降低相关。通过分析人类 T 细胞中的 H3K27 乙酰化谱，我们发现了一种含有自身免疫相关 SNP 的RASGRP1增强子。该增强子的 CRISPR-Cas9 破坏导致 RasGRP1 表达降低，并减少 RUNX1 和 CBFB 转录因子的结合。通过分析自身免疫患者，我们检测到 CD4 ⁺ T 细胞中 RUNX1 表达减少。最后，我们将 RUNX1 与RASGRP1的转录调节机制联系起来，揭示了调节 RasGRP1 表达的关键回路，这对于预防炎症性疾病至关重要。

更新日期：2020-10-16

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