A cytoplasmic index for quantifying immune-related A-to-I RNA editing

Area of Science:

• Molecular Biology
• Immunology
• Genomics

Background:

• The immune system must distinguish self from non-self, with endogenous RNA posing a challenge.
• ADAR1-mediated RNA editing suppresses immune activation by endogenous double-stranded RNA (dsRNA).
• Global RNA editing indices are limited by nuclear pre-mRNA edits, lacking immune relevance.

Purpose of the Study:

• To develop a refined metric for quantifying immune-relevant RNA editing.
• To assess the utility of the cytoplasmic editing index (CEI) for profiling ADAR1 activity.
• To enable broader adoption of high-quality RNA editing analysis.

Main Methods:

• Quantification of RNA editing specifically within inverted Alu repeats in cytoplasmic transcripts.
• Analysis of over 25,000 RNA-sequencing samples.
• Development of an open-source, cloud-native pipeline for reproducible analysis.

Main Results:

• CEI effectively captures ADAR1p150 activity, outperforming global editing indices in sensitivity and signal-to-noise.
• CEI enables sharper tissue-specific profiling and enhanced detection of infection-induced editing changes.
• CEI demonstrates a stronger association with cancer prognoses.

Conclusions:

• CEI offers a refined metric for immune-relevant RNA editing, revealing obscured tissue- and disease-specific landscapes.
• The open-source pipeline facilitates scalable adoption of high-quality editing analysis.
• This approach advances the study of ADAR1 in immunity, infection, and cancer, with potential for biomarker and therapeutic development.