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Role of lncRNA mediated R-loops in CTCF boundary function and AML genome organization

Award Number: R01CA260729
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/03/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Role of lncRNA mediated R-loops in CTCF boundary function and AML genome organization - Abstract: Acute myeloid leukemia (AML) is a heterogeneous disorder of hematopoietic stem and progenitor cells (HSPCs) associated with sequential acquisition of driver gene mutations. These mutations often lead to altered genome organization and transcriptional programs that perturb HSC self-renewal and differentiation. Recently, we discovered that HOTTIP, a posterior HOXA-associated long non-coding RNA (lncRNA), remodels CTCF- defined topologically associated domains (TADs). This remodeling regulates the homeotic gene-associated leukemic transcription program and facilitates AML leukemogenesis, driven by MLL rearrangement (MLLr+) or NMP1 mutation (NPM1C+). One of the top HOTTIP-regulated transcription motifs in AML is CTCF-binding sites (CBSs), suggesting a novel function of HOTTIP in regulating CTCF-mediated genome organization and AML pathogenesis. Indeed, combined RNA-seq, ChIRP-seq, and CTCF ChIP-seq analyses revealed that HOTTIP co-occupied with CTCF in a subset of the AML genome, including HOXA and WNT/β-catenin target gene loci, for their activation. However, it remains unknown whether and how HOTTIP lncRNA directly regulates CTCF- directed genome organization to promote leukemic transcription networks and leukemogenesis. Our preliminary data showed that HOTTIP is capable of directly interacting with key TAD boundary CBSs in the HOXA and WNT target loci via formation of an R-loop structure. We hypothesize that HOTTIP activation mediates aberrant R- loop formation in CBSs to stratify CTCF chromatin boundary for reprograming AML TADs and leukemic transcription networks, leading to HSPC perturbation and leukemogenesis. To test this hypothesis, we will focus on the impact of the altered CTCF TAD boundary and R-loop formation upon HOTTIP activation on AML genome regulation and gene transcription output. In this proposal we will test the importance of the HOTTIP activation- mediated aberrant R-loop formation in modulating the CTCF boundary activity and transcriptional regulation in AML. Specifically, we will identify and characterize critical HOTTIP-regulated CTCF chromatin boundaries in the AML genome. We will then define the novel role of R-loops in HOTTIP-mediated CTCF chromatin boundary definition and genome organization. Finally, we will assess the impact of the HOTTIP-mediated aberrant R-loop formation at specific TAD boundaries on leukemogenesis and HSPC 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 = $626,361 )
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Biology Research	001	4	2/14/2025	NON-COMPETING CONTINUATION	$0
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Biology Research	000	4	11/20/2024	NON-COMPETING CONTINUATION	$563,725
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Biology Research	002	4	6/18/2025	NON-COMPETING CONTINUATION	$62,636
														Subtotal = $626,361

Issue Date FY: 2024 ( Subtotal = $595,044 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Biology Research	001	3	4/16/2024	NON-COMPETING CONTINUATION	$31,319
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Biology Research	000	3	11/14/2023	NON-COMPETING CONTINUATION	$563,725
														Subtotal = $595,044

Issue Date FY: 2023 ( Subtotal = $613,836 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Biology Research	000	2	11/28/2022	NON-COMPETING CONTINUATION	$563,727
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Biology Research	001	2	3/14/2023	NON-COMPETING CONTINUATION	$50,109
														Subtotal = $613,836

Issue Date FY: 2022 ( Subtotal = $641,950 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Biology Research	000	1	12/3/2021	NEW	$641,950
														Subtotal = $641,950

Grand Total All Awards = $2,477,191

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Role of lncRNA mediated R-loops in CTCF boundary function and AML genome organization

Award Number: R01CA260729

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/03/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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