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Reactivation of an early embryonic program in FSHD and cancer

Award Number: F32CA254805
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Reactivation of an early embryonic program in FSHD and cancer - PROJECT SUMMARY/ABSTRACT Master regulator transcription factors promote genetic programs required for developmental processes, enabling precise control of cell fate. Because of their importance, their misexpression in the wrong cellular context can lead to disease. One example of a transcription factor involved in such complex regulation is Double Homeobox Protein 4 (DUX4), which is crucial for early embryonic development. DUX4 is briefly expressed at the 4-cell stage in the human embryo where it activates early zygotic gene expression; whereas mis-expression of DUX4 in skeletal muscle is toxic, causing facioscapulohumeral muscular dystrophy (FSHD). We also recently identified DUX4 re-activation in multiple solid cancers. Ectopic DUX4 expression in both FSHD and cancer occurs at low levels and in very few cells but is sufficient to drive an embryonic gene program. As part of this gene network, we find that DUX4 activates histone demethylase KDM4E and histone variants H3.X and H3.Y, resulting in changes to the chromatin landscape. Furthermore, a brief pulse of DUX4 triggers long-term protein suppression, including that of Major Histocompatibility Complex class I (MHC-I) immune response proteins that may contribute to cancer immune evasion. I hypothesize that the transient expression of DUX4 initiates a perdurant naïve developmental state by establishing a chromatin memory and activating long-lived intermediary regulatory factors, and that the perdurance of the DUX4 network is a major driver of disease pathogenicity. I propose to identify epigenetic and post-transcriptional mechanisms by which DUX4 promotes its developmental program, resulting in cellular dysfunction in models of FSHD and cancer. Given the low levels and sporadic nature of endogenous DUX4 expression in FSHD and cancer cells, downstream mechanisms are difficult to elucidate in disease cell lines. My approach uses focused experiments in cellular models of DUX4 expression to elucidate epigenetic dynamics and post-transcriptional mechanisms activated by DUX4. I will: 1) use genome- wide approaches to identify epigenetic mechanisms induced by DUX4 that alter the chromatin landscape and regulate gene expression; 2) perform a targeted proteomics screen to determine the functional relevance of DUX4-target genes involved in the ubiquitin-proteasome pathway; and 3) carry out a large-scale CRISPR/Cas9 screen to identify genes responsible for MHC-I suppression. My goal is to understand the downstream biological consequences of DUX4 expression in disease and to identify mechanisms induced by DUX4 that contribute to perdurance of its early developmental program. This program consists of common molecular mechanisms employed in both early embryo development and tumorigenesis—including epigenetic reprogramming, global changes in gene expression, and immune suppression. Through a better understanding of the role DUX4 plays in development and disease, we may reveal novel diagnostic and therapeutic targets.


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: 2024 ( Subtotal = -$2,708 )
2024	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	001	4	9/23/2024	NON-COMPETING CONTINUATION	-$2,708
2024	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	000	4	2/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = -$2,708

Issue Date FY: 2023 ( Subtotal = $69,766 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	000	4	11/3/2022	NON-COMPETING CONTINUATION	$69,802
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	001	4	5/10/2023	NON-COMPETING CONTINUATION	$1,990
2023	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	002	2	5/15/2023	NON-COMPETING CONTINUATION	-$2,026
														Subtotal = $69,766

Issue Date FY: 2022 ( Subtotal = $67,582 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	004	3	8/4/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$100
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	001	2	11/29/2021	NON-COMPETING CONTINUATION	$1,080
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	002	2	6/9/2022	NON-COMPETING CONTINUATION	-$42,714
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	003	3	6/9/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$43,806
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	000	2	11/5/2021	NON-COMPETING CONTINUATION	$65,310
														Subtotal = $67,582

Issue Date FY: 2020 ( Subtotal = $64,926 )
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	000	1	6/19/2020	NEW	$64,926
														Subtotal = $64,926

Grand Total All Awards = $199,567

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Reactivation of an early embryonic program in FSHD and cancer

Award Number: F32CA254805

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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