Sunday, November 24, 2024 11/24/2024

Deciphering the Role of Aberrant Endogenous Retroviral Expression in Onco-histone Driven Glioma

Award Number: R01NS116361
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Abstract

ABSTRACT The polycomb repressive complex 2 (PRC2) is recurrently disrupted in brain cancer; a complex required for depositing the repressive histone modification, H3K27 tri-methylation (H3K27me3). Maintenance of PRC2 function is important for repression of genes and repetitive elements, providing a safe-guard against aberrant transcription. PRC2 is essential for proper embryonic cell maintenance, neural stem cell differentiation, and overall brain development. How PRC2 dysfunction and aberrant H3K27me3 levels contributes to brain tumorigenesis is unclear. As a model of PRC2 dysfunction in brain tumors, our lab investigates midline high grade gliomas (HGG) that harbor frequent histone H3 lysine 27 to methionine mutations (denoted H3K27M). Expression of H3K27M impairs PRC2 function and results in a global loss of H3K27me3; a defining feature of these brain tumors. Using isogenic glioma models in which H3K27M is deleted, we found that the H3K27M results in a global increase in a mark of active transcription, H3K27 acetylation (H3K27ac) (Krug et al., Cancer Cell, 2019). Surprisingly, global H3K27ac has minimal effects on gene transcription. Instead, we discovered a novel mechanism of H3K27ac associated transcription of repetitive DNA elements, namely Type-H human endogenous retroviral (HERV) sequences. We hypothesize that: 1) HERV activation plays a functional role in the biology of H3K27M-driven glioma, and 2) Amplification of HERV expression represents a novel anti-cancer strategy against tumors with global loss of H3K27me3. To test this hypothesis we propose three specific aims to: 1) Decipher the mechanisms of HERV transcriptional activation in H3K27M-driven glioma, 2) Determine the impact of HERV expression on H3K27M-glioma cell identity and tumor formation, and 3) Delineate the mechanisms of HERV detection and response in H3K27M-glioma. Collectively these experiments will reveal mechanistic insight into the role of HERV expression in high-grade glioma and cellular vulnerabilities created by H3K27M mutations.


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 = $558,855 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/17/2024	NON-COMPETING CONTINUATION	$40,330
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/8/2023	NON-COMPETING CONTINUATION	$518,525
														Subtotal = $558,855

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	2/27/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$329,104
2023	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2021	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	2/27/2023	NEW	-$329,104
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $576,139 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	9/5/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$576,139
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	9/8/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/5/2022	NEW	$0
														Subtotal = $576,139

Issue Date FY: 2021 ( Subtotal = $398,540 )
2021	2021	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/30/2020	NEW	$398,540
														Subtotal = $398,540

Grand Total All Awards = $1,533,534

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Deciphering the Role of Aberrant Endogenous Retroviral Expression in Onco-histone Driven Glioma

Award Number: R01NS116361

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer