Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Mechanisms of post-transcriptional regulation of splicing factors

Award Number: R01GM138541
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: 07/06/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2026

Group Awards By:

View Award Description

Mechanisms of post-transcriptional regulation of splicing factors - PROJECT SUMMARY Alternative RNA splicing enables generation of different spliced mRNA isoforms that can encode functionally distinct proteins. Splicing factors (SFs) are RNA-binding proteins that regulate splicing in a dose-dependent manner and are frequently dysregulated in diseases. Serine/arginine-rich (SR) proteins (SRSF1 to 12, and SR- like members TRA2α, TRA2β) are a family of essential SFs causatively implicated in a wide range of human pathologies. Elucidating how SR proteins are regulated is crucial to advance our understanding of the fundamental processes that control gene expression in eukaryotes and to target diseases with SF defects. Here, we will focus on post-transcriptional regulation as an important modulator of SR protein expression, and a potentially actionable pathway for tool and therapeutics development. SR protein genes contain ultra-conserved non-coding exons, called poison-exons (PEs), which control SR protein auto-regulation. Conservation of PE sequences across species suggests their importance in regulating SFs. However, how PEs regulate gene expression and maintain broader SF homeostasis, and how they contribute to fundamental cell functions remain poorly understood. We hypothesize that PEs play a critical role in maintaining a tight regulation of SF levels, which is necessary for normal cell functions. Aim 1 will define the mechanisms of SR protein regulation and cross-regulation via PEs using splicing reporter minigenes, a CRISPR/Cas9 library targeting SFs, and long-read RNA sequencing. By identifying the SR proteins and SFs that are interconnected and co-regulated through PE splicing, these findings will provide a comprehensive map of the SR protein regulatory network and will uncover novel principles of post-transcriptional gene regulation. Aim 2 will define the functional role of SR protein PEs in development and cell differentiation using CRISPR/Cas9 to delete PE sequences in vivo in mouse embryos and in vitro in human cell differentiation models. These findings will reveal cell types and cellular states that require PEs to function normally, as well as PE targets in vivo and in vitro. Aim 3 will develop approaches to modulate PE splicing and SR protein levels. These approaches will be used to infer SR protein binding rules, and to probe PE function in relevant disease models. The proposed aims leverage our lab’s expertise in developing tools and models to study splicing dysregulation in diseases. Completion of these aims will identify novel molecular mechanisms by which PEs regulate SF homeostasis and cellular functions, and provide new tools to manipulate SR protein levels. The regulatory mechanisms uncovered here are likely to have broad relevance to many SFs, the majority of which contain PEs. Manipulating SF levels by targeting PEs could lead to therapeutic approaches for diseases with SF defects, such as neurological disorders, cardiac myopathies, diabetes, lupus, or cancer.


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 = $0 )
2026	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	5	8/5/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $425,252 )
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	5	5/13/2024	NON-COMPETING CONTINUATION	$425,252
														Subtotal = $425,252

Issue Date FY: 2023 ( Subtotal = $425,252 )
2023	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	4	4/7/2023	NON-COMPETING CONTINUATION	$425,252
														Subtotal = $425,252

Issue Date FY: 2022 ( Subtotal = $425,252 )
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	3	3/31/2022	NON-COMPETING CONTINUATION	$382,724
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	001	3	8/3/2022	NON-COMPETING CONTINUATION	$42,528
														Subtotal = $425,252

Issue Date FY: 2021 ( Subtotal = $425,252 )
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	2	4/9/2021	NON-COMPETING CONTINUATION	$425,252
														Subtotal = $425,252

Issue Date FY: 2020 ( Subtotal = $425,254 )
2020	2020	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	1	7/6/2020	NEW	$425,254
														Subtotal = $425,254

Grand Total All Awards = $2,126,262

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Mechanisms of post-transcriptional regulation of splicing factors

Award Number: R01GM138541

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: 07/06/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer