Charting and probing the activity of ADARs in human development and cell-fate specification

Amir Dailamy, Weiqi Lyu, Sami Nourreddine, Michael Tong, Joseph Rainaldi, Daniella McDonald, Rebecca Panwala, Alysson Muotri, Michael S. Breen, Kun Zhang and Prashant Mali ()
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Amir Dailamy: University of California San Diego
Weiqi Lyu: University of California San Diego
Sami Nourreddine: University of California San Diego
Michael Tong: University of California San Diego
Joseph Rainaldi: University of California San Diego
Daniella McDonald: University of California San Diego
Rebecca Panwala: University of California San Diego
Alysson Muotri: University of California San Diego
Michael S. Breen: Icahn School of Medicine at Mount Sinai
Kun Zhang: University of California San Diego
Prashant Mali: University of California San Diego

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Adenosine deaminases acting on RNA (ADARs) impact diverse cellular processes and pathological conditions, but their functions in early cell-fate specification remain less understood. To gain insights here, we began by charting time-course RNA editing profiles in human organs from fetal to adult stages. Next, we utilized hPSC differentiation to experimentally probe ADARs, harnessing brain organoids as neural specific, and teratomas as pan-tissue developmental models. We show that time-series teratomas faithfully recapitulate fetal developmental trends, and motivated by this, conducted pan-tissue, single-cell CRISPR-KO screens of ADARs in teratomas. Knocking out ADAR leads to a global decrease in RNA editing across all germ-layers. Intriguingly, knocking out ADAR leads to an enrichment of adipogenic cells, revealing a role for ADAR in human adipogenesis. Collectively, we present a multi-pronged framework charting time-resolved RNA editing profiles and coupled ADAR perturbations in developmental models, thereby shedding light on the role of ADARs in cell-fate specification.

Date: 2024
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DOI: 10.1038/s41467-024-53973-0

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