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Developmental Regulation of Gene Expression by Long Undecoded Transcript Isoforms

Award Number: R01GM140005
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Developmental Regulation of Gene Expression by Long Undecoded Transcript Isoforms - PROJECT SUMMARY Dynamic gene expression programs drive essential biological processes including cellular differentiation and stress response pathways. During these processes, cells must simultaneously activate and repress distinct clusters of genes to facilitate the necessary shift in proteome synthesis. How gene repression is achieved amidst widespread transcriptional activation is not well understood. My lab has recently discovered a regulatory mechanism in budding yeast meiosis that achieves such coordination. Central to this mechanism is the transcription factor-driven expression of an alternative mRNA isoform called LUTI (Long Undecoded Transcript Isoform) from a distal gene promoter. This mRNA cannot produce functional protein due to competitive upstream open reading frames (uORFs) in its extended 5' leader. Instead, its transcription serves to repress the canonical mRNA transcription in cis through chromatin modifications, ultimately leading to inhibition of protein synthesis. Therefore, transcription of these mRNAs, despite carrying a full coding region, can directly cause gene repression. Consequently, a single transcription factor can synchronously activate and repress protein synthesis for distinct sets of genes, depending whether it binds to a canonical or a LUTI promoter, respectively. Furthermore, this mechanism is tunable and reversible, making it ideal for fluid cell state transitions that rely on dynamic changes in gene expression. The LUTI-based mechanism is neither limited to meiosis nor restricted to budding yeast, as it occurs during the unfolded protein response and is conserved in human cells. Importantly, the two essential branches of this regulation are both associated with human disease. First, misregulation of alternative transcription start sites is widespread across multiple cancers. Second, disruption of uORF expression is linked to a variety of disorders ranging from gonadal dysgenesis to melanoma. Therefore, dissecting the mechanism and biological scope of LUTI-based regulation is critical for our understanding of how cells control their gene expression programs, and how mistakes in this process can lead to pathological states. This proposal seeks to address fundamental questions regarding the mechanism and function of LUTI-based regulation in yeast and human cells. Experiments proposed in aim 1 will investigate how transcriptional repression is achieved by activation of LUTI promoters during meiosis and the unfolded protein response, where LUTIs are pervasively expressed. Experiments proposed in aim 2 will elucidate how the LUTI-based regulation is integrated into larger signaling networks to ensure precise and robust cell state transitions. Finally, experiments proposed in aim 3 will determine the evolutionarily conserved aspects of LUTI-based regulation and uncover the biological roles of LUTIs during human embryonic stem cell differentiation. The combination of studies described in this proposal will illuminate how cells dynamically control their gene expression programs with transcription factor-driven waves of coordinated gene activation and repression, not anticipated prior to our discovery of LUTIs.


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: 2025 ( Subtotal = $0 )
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	4	5/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $313,908 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	001	4	6/20/2024	NON-COMPETING CONTINUATION	$31,391
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	4	11/16/2023	NON-COMPETING CONTINUATION	$282,517
														Subtotal = $313,908

Issue Date FY: 2023 ( Subtotal = $315,010 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	3	12/5/2022	NON-COMPETING CONTINUATION	$283,509
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	001	3	3/31/2023	NON-COMPETING CONTINUATION	$31,501
														Subtotal = $315,010

Issue Date FY: 2022 ( Subtotal = $316,060 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	001	2	8/3/2022	NON-COMPETING CONTINUATION	$31,606
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	2	1/13/2022	NON-COMPETING CONTINUATION	$284,454
														Subtotal = $316,060

Issue Date FY: 2021 ( Subtotal = $330,729 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	1	12/25/2020	NEW	$330,729
														Subtotal = $330,729

Grand Total All Awards = $1,275,707

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Developmental Regulation of Gene Expression by Long Undecoded Transcript Isoforms

Award Number: R01GM140005

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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