Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Ras guanine nucleotide exchange factor 1 (RasGRP1) is critical for lymphocyte signaling.
• RasGRP1 deficiency causes immune defects and is linked to autoimmunity.
• Regulation of RasGRP1 levels and its role in autoimmunity are not fully understood.

Purpose of the Study:

• To investigate the regulation of RasGRP1 expression.
• To determine the role of RasGRP1 dosage in autoimmunity.
• To elucidate the molecular mechanisms linking RasGRP1 to inflammatory disease.

Main Methods:

• Studied Rasgrp1 deletion in mice to assess T lymphocyte development and inflammatory disease.
• Analyzed RASGRP1 levels in CD4+ T cells from human patients with autoimmunity.
• Utilized H3K27 acetylation profiling and CRISPR-Cas9 to investigate a RASGRP1 enhancer.
• Assessed RUNX1 expression in patients with autoimmunity.

Main Results:

• Diminished Rasgrp1 expression in mice led to defective T lymphocyte selection and inversely correlated with inflammatory disease severity.
• Autoimmune patients exhibited decreased RASGRP1 levels in CD4+ T cells during active inflammation.
• A RASGRP1 enhancer with autoimmunity-associated SNPs was identified; its disruption reduced RasGRP1 expression and RUNX1/CBFB binding.
• Reduced RUNX1 expression was observed in CD4+ T cells of autoimmune patients.

Conclusions:

• RasGRP1 dosage is critical for preventing inflammatory disease.
• A RUNX1-dependent transcriptional circuit regulates RASGRP1 expression.
• Dysregulation of this circuit contributes to autoimmunity.