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ILF2 and ILF3 shield transcripts from RNA editing to enable human cell fate transitions

ABSTRACT: Chromatin regulation and RNA processing are both fundamental for establishing cell identity, yet how they interact to direct cell fate remains unclear. To uncover factors that coordinate this interplay, we screened dual DNA- and RNA-binding proteins (DRBPs) and identified ILF2 and ILF3 as critical regulators of human cell fate. We show that ILF2 and ILF3 control human, but not mouse, gastrulation and maintain the self-renewal of adult progenitor cells across all three germ layers. Mechanistically, ILF2 and ILF3 interact with and inhibit the RNA-editing enzyme ADAR, which catalyzes adenosine-to-inosine conversion in primate-specific repetitive elements. Acute degradation of the ILF2-ILF3 complex triggers widespread RNA misediting and missplicing of transcripts encoding key cell fate regulators. These misedited transcripts are degraded, destabilizing the proteome and rewiring the epigenetic landscape of stem and progenitor cells. Our findings reveal a human-specific mechanism linking RNA processing to chromatin regulation and identify an evolutionary safeguard that prevents aberrant RNA editing and retrotransposon activation, enabling human cell fate transitions.

INSTRUMENT(S): Orbitrap Ascend

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pluripotent Stem Cell

SUBMITTER: Joshua Coon

LAB HEAD: Joshua J. Coon

PROVIDER: PXD061192 | Pride | 2025-02-26

REPOSITORIES: pride

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			Action	DRS
	20240611_LYC_Ystone_iPSC_0day_1.raw	Raw
	20240611_LYC_Ystone_iPSC_0day_2.raw	Raw
	20240611_LYC_Ystone_iPSC_0day_3.raw	Raw
	20240611_LYC_Ystone_iPSC_1day_1.raw	Raw
	20240611_LYC_Ystone_iPSC_1day_2.raw	Raw

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