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Dissecting the transcription factor networks controlling fetal T-lineage differentiation

Award Number: F32AI181504
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Dissecting the transcription factor networks controlling fetal T-lineage differentiation - Project Summary/Abstract Multiple sequential waves of T-cell development in the fetal and post-natal thymus give rise to discrete T cell subsets, each with its own functional properties. Compared with all subsequent waves, the first wave of T-cell differentiation proceeds very rapidly and gives rise to unique lineages of innate lymphocytes and innate-like γδT cells. These cell-intrinsic characteristics of first-wave fetal thymocytes suggests that they have their own separate developmental program. T-cell development is coordinated by a dynamic set of transcription factors (TFs) with stage-specific activity, through a complex network of regulatory interactions. Significant progress has been made in recent years in understanding the T-cell differentiation program; however, whether first-wave fetal thymocytes use the same T-lineage differentiation program is unknown. Through direct comparison of the transcriptional program of murine adult and first-wave fetal thymocytes by single-cell RNA-seq, as well as reanalysis of a public scRNA-seq atlas of thymic organogenesis (GSE107910; Kernfeld et al, 2018), I observed that the first wave of fetal T-cell development occurs simultaneously along two separate trajectories. One trajectory follows the well-established T-cell development pathway, while the other is used exclusively by first- wave fetal thymocytes and gives rise to innate lymphocytes and innate-like γδT cells. Cells on this trajectory appear to use a distinct differentiation program consisting of many TFs typically associated with innate lymphocyte development—including PLZF and Lmo4—alongside shared T/innate TFs, such as TCF1, GATA3, and Bcl11b; as well as GATA1 and Meis1, two TFs with no known role in differentiation of either lineage, and the pan-fetal hematopoiesis regulator Lin28b. I hypothesize that this computationally-inferred population consists of immediate precursors of innate lymphoid and innate-like γδT-lineage cells, and that their differentiation is guided by this unique TF network. In Aim 1, I will fate map the progeny of this hypothesized innate lymphocyte/innate-like γδT cell precursor. Within thymocytes, it is the only population that expresses Gata1; therefore I will use Gata1CreERT2 x Rosa26lsl-tdT mice to fate map the progeny of Gata1- expressing cells at embryonic gestational day E13.5. Additionally, I will use clonal barcoding and scRNA-seq at multiple timepoints to construct a full lineage hierarchy of fetal thymocyte differentiation, and I will perform scATAC-seq to determine whether lineage priming is occurring in this population or in an upstream precursor at the level of chromatin accessibility. In Aim 2, I will use CRISPR/Cas9 to delete constituent factors in the innate lymphocyte/innate-like γδT-lineage program in fetal progenitors and assess the impact of each on developmental speed and lineage choice. I will also perform scRNA-seq on TF-deleted cells in order to identify the effect each TF has on the overall program, including how it regulates other members of the program. In this way, I will use perturbations to construct a network of the regulatory interactions dictating the characteristic developmental speed and lineage choice of first-wave thymocytes.


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 = $78,040 )
2026	2026	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	1/21/2026	NON-COMPETING CONTINUATION	$78,040
														Subtotal = $78,040

Issue Date FY: 2025 ( Subtotal = $75,520 )
2025	2025	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	12/20/2024	NON-COMPETING CONTINUATION	$74,284
2025	2025	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	2	8/4/2025	NON-COMPETING CONTINUATION	$1,236
														Subtotal = $75,520

Issue Date FY: 2024 ( Subtotal = $73,828 )
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	1	5/14/2024	NEW	$4,748
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	11/24/2023	NEW	$69,080
														Subtotal = $73,828

Grand Total All Awards = $227,388

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Dissecting the transcription factor networks controlling fetal T-lineage differentiation

Award Number: F32AI181504

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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