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Connecting perturbations of RNA binding proteins to their consequences

Award Number: F32HG012307
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Connecting perturbations of RNA binding proteins to their consequences - PROJECT SUMMARY/ABSTRACT Alternative splicing allows multiple gene products to be generated from a single gene, and contributes to transcriptomic diversity across tissues, development, and individuals. Given that most genes undergo alternative splicing, the disruption of splicing is a common contributor to disease. Pathology can result through mutations affecting the splicing of particular genes as well as broad splicing defects that affect many genes. Advances in sequencing technology have greatly simplified the problem of identifying the splicing products present in a given tissue and determining how splicing is perturbed in diseases states. But the problem remains to extract actionable interpretations from the hundreds or thousands of splicing changes that even a single sequencing experiment might reveal. The goal of this project is to understand how perturbations of splicing regulators connect to the resulting changes in splicing. I will consider both variation at RNA-binding protein target sites and disruption of the RBPs themselves. I will first consider the connection between short tandem repeat (STR) variation and splicing. Given that many of the most abundant STRs in the genome match the sequence preferences of important splicing factors, I will leverage sequencing data spanning hundreds of individuals to determine whether these highly mutable sequences represent a frequently ignored source of splicing variation. I will then consider the regulatory characteristics of RBPs themselves. I will first reframe the approach commonly used to integrate RBP binding and splicing data as a flexible linear model which can incorporate additional information and confounders. I will then apply this to recent ENCODE panel of RBP binding and knockdown data to infer the networks of splicing events regulated by a given RBP. I will then seek to use these networks to interpret patterns of altered splicing in disease states. I will carry out this work under the mentorship of Christopher Burge at the Massachusetts Institute of Technology (MIT), a leader in the field of alternative splicing. Given the Burge lab’s long track record of strong computational and experimental work, this will provide an ideal environment for both carrying out this research and developing the skills I will need for an independent career as a computational biologist. The proposed training will involve frequent interaction with experts in the study of RNA binding proteins and splicing, including the research groups that generated many of the datasets I will study, such as the Graveley and Yeo labs. Through this work I will develop further technical expertise in a number statistical and computational approaches and be immersed in the biology of splicing. I will have access to the experience and expertise I will need to transition from the evolutionary genomics of my PhD to the study of RNA processing and its regulation


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 = -$215 )
2025	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	3	9/24/2025	NON-COMPETING CONTINUATION	-$215
														Subtotal = -$215

Issue Date FY: 2024 ( Subtotal = $78,892 )
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	3	11/16/2023	NON-COMPETING CONTINUATION	$73,772
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	001	3	7/23/2024	NON-COMPETING CONTINUATION	$5,120
														Subtotal = $78,892

Issue Date FY: 2023 ( Subtotal = $71,792 )
2023	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	2	11/18/2022	NON-COMPETING CONTINUATION	$69,802
2023	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	001	2	9/22/2023	NON-COMPETING CONTINUATION	$1,990
														Subtotal = $71,792

Issue Date FY: 2022 ( Subtotal = $67,582 )
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	002	1	7/1/2022	NEW	$1,192
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	1	11/19/2021	NEW	$66,390
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	001	1	11/19/2021	NEW	$0
														Subtotal = $67,582

Grand Total All Awards = $218,051

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Connecting perturbations of RNA binding proteins to their consequences

Award Number: F32HG012307

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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