Charting and probing the activity of ADARs in human development and cell-fate specification.
Publication Year:
2024
PubMed ID:
39537590
Funding Grants:
Public Summary:
Adenosine deaminases acting on RNA (ADARs) play a role in various cellular processes and diseases, but their functions in early cell development are not well understood. The research explored how ADARs influence cell-fate decisions by examining RNA editing patterns in human organs from fetal to adult stages. Using human stem cell differentiation and models like brain organoids and teratomas to study ADARs. They found that teratomas mimic fetal development, and by using CRISPR to knock out ADARs, observed a global decrease in RNA editing across all cell types. Interestingly, ADAR knockout led to an increase in fat cell formation, highlighting its role in human fat development. This study provides new insights into how ADARs contribute to early cell-fate decisions.
Scientific 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.
