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Uncovering the Principles of Transcription Factor Cooperativity in Human White Blood Cells

Award Number: F31AI203664
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/19/2027
PERIOD OF PERFORMANCE END DATE: 02/18/2028

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Uncovering the Principles of Transcription Factor Cooperativity in Human White Blood Cells - Project Summary: Precise tuning of gene expression is essential for hematopoiesis and a properly functioning immune system. In humans, expression control relies on enhancers – non-coding regions that carry regulatory information in the form of transcription factor binding sites (TFBSs). TFs have been shown to work cooperatively to tune transcription and disruption of their function, e.g. via mutations to their binding sites, is linked to blood disorders like Hemophilia, autoimmune conditions, and hematopoietic malignancies such as leukemias and lymphomas. Since a typical enhancer encodes a dozen or more putative TFBSs that may or may not interact cooperatively, it is challenging to know a priori which TFBS disruptions will lead to transcriptional dysregulation and disease. In general, the regulatory complexity encoded in enhancers makes it difficult to determine the individual contributions of specific TFs to enhancer function and downstream gene expression. For combinatorial TF action, inference is further complicated by the sheer number of possible TFBS combinations and configurations an enhancer can adopt (the human genome encodes > 1500 TFs). While we know that individual TFs (such as PU.1) interact with secondary TFs to specify the lymphoid lineage, we lack insight into the mechanistic underpinnings of such cooperativity. Here, I propose to establish a high-throughput reporter assay called CORTA, for Combinatorial reporter of TF activity, that accurately quantifies the contribution of distinct TF combinations to enhancer activity in a systematic manner while ensuring human interpretable results. For this, I developed a copying mechanism that generates identical repeats of short sequences that contain one fixed BS (TF1) next to a random site that allows for the unbiased enrichment of a second TF. This generates minimalistic sequences of similar length and BS density as native enhancers, yet without the endogenous confounder of having dozens of different TFBSs (never more than 2 TFs). Probing minimal enhancer activity using ‘self-transcribing’ reporters in both episomal and genome- integrated contexts, I will quantify and compare the transcriptional output linked to specific TF pairs and its dependency on BS density and affinity. Preliminary data I generated demonstrates the feasibility of CORTA. I will use CORTA as a ‘transcriptional sensor’ to 1) detect TF combinations that drive cell type-specific expression across human white blood cells, and 2) to identify cooperative TF pairs that control switch-like expression programs (e.g. ON/OFF) during immune cell stimulation. The proposed research will generate a comprehensive map of how the combinatorial action of TFs shapes both steady-state and dynamic gene expression programs within the lymphoid lineage. By revealing regulatory principles, this data will contribute to advancing immune- related therapies – enhancing interpretability of non-coding genetic disorders and generating candidate sequences for next generation drivers of immunotherapies. 1


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 = $46,548 )
2026	2026	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	8/19/2026	NEW	$46,548
														Subtotal = $46,548

Grand Total All Awards = $46,548

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Uncovering the Principles of Transcription Factor Cooperativity in Human White Blood Cells

Award Number: F31AI203664

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/19/2027

PERIOD OF PERFORMANCE END DATE: 02/18/2028

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