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DEFINING THE ROLE OF CO-TRANSCRIPTIONAL REGULATION IN HUMAN CELL FATE TRANSITIONS

Award Number: R01HD121587
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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DEFINING THE ROLE OF CO-TRANSCRIPTIONAL REGULATION IN HUMAN CELL FATE TRANSITIONS - PROJECT SUMMARY Precise regulation of cell fate specification during early embryogenesis is essential for proper tissue and organ formation, and its disruption leads to congenital malformations. However, the gene regulatory pathways controlling these early developmental decisions—particularly in humans—remain poorly understood. This proposal investigates a novel, primate-specific mechanism of cell fate control mediated by the dual-function DNA/RNA-binding protein ILF3. Identified through genome-wide screens in human pluripotent stem cells (PSCs), ILF3 is required for proper exit from pluripotency and lineage specification in human and primate—but not mouse—PSCs. Our data show that ILF3 interacts with and inhibits the RNA editing enzyme ADAR1 to limit adenosine-to-inosine (A-to-I) editing at primate-specific Alu elements, thereby preserving accurate splicing of developmental transcripts. These findings implicate ILF3 as a critical regulator of transcriptome fidelity in early primate development and introduce a novel paradigm where species-specific RNA processing fidelity serves as a developmental checkpoint. To define the developmental and mechanistic roles of ILF3, we propose three integrated aims. In Aim 1, we will use cross-species gastruloid models from human, chimpanzee, rhesus monkey, and mouse to assess ILF3's role in early lineage transitions and test whether it defines a primate- specific pathway in mammalian development. In Aim 2, we will map nascent RNA editing following acute ILF3 depletion using SLAM-seq and identify the protein domains mediating ILF3-ADAR1 interaction, linking RNA editing regulation to cell fate control. In Aim 3, we will define how ILF3 impacts RNA processing at key developmental genes by integrating splicing analysis and quantitative proteomics, uncovering direct effectors of lineage specification. Moreover, we will establish a causal link between expression of mis-edited and mis-spliced developmental regulators and proper gastruloid formation through rescue experiments. This research will uncover a previously unrecognized RNA-based regulatory mechanism controlling early primate development and provide insight into how defects in RNA editing and splicing may contribute to congenital disease. By establishing a functional framework for ILF3 in safeguarding human cell fate transitions, this work will inform future strategies for therapeutic intervention in developmental disorders, directly supporting NICHD's mission to understand and treat the origins of birth defects.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $596,684 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	1	5/27/2026	NEW	$596,684
														Subtotal = $596,684

Grand Total All Awards = $596,684

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DEFINING THE ROLE OF CO-TRANSCRIPTIONAL REGULATION IN HUMAN CELL FATE TRANSITIONS

Award Number: R01HD121587

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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