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Mutual reinforcement between somatic mutations and transcription factors in clonal hematopoiesis

Award Number: R01DK132286
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/ Abstract Recent highthroughput exome sequencing has revealed various somatic mutations in individuals with clonal hematopoiesis (CH) and myelodysplastic syndromes (MDS) patients. Among these mutations, C-to-T mutations is among the most common type of single mutations observed in CH and MDS. It remains yet to be explained why C-to-T mutations are preferentially enriched in CH and MDS and how the C-to-T transition alters hematopoietic stem and progenitor cells (HSPCs) fitness and leads to aberrant clonal expansion. By combining in vitro biochemical and structural analyses with epigenomic profiling of bone marrow samples from MDS patients, the team discovered a previously-underappreciated mutual reinforcement between C-to-T transition and genomic binding of transcription factors (TFs), which contributes to the clonal expansion of HSPCs and aggravate CH and MDS. In Aim1, the team will use genetically-modified mouse models and CRISPR/Cas9- based genome editing methods to probe the causality between C-to-T transition and TF binding in HSPCs. In Aim 2, the team will test how the C-to-T transition and DNA methylation deregulation reshape the genomic distribution of TFs, subsequently altering downstream transcriptional outputs to cause clonal expansion in HSPCs. In parallel, the team will use HSPCs purified from CH and MDS patients to further validate findings made ex vivo and in rodent models. The proposed studies are anticipated to significantly advance our mechanistic understanding on how TFs shape the genome and how somatic mutations alter transcriptional regulation in HSPCs. From a translational perspective, discoveries made from this study will lead to the identification of therapeutic vulnerabilities for CH and MDS treatment.


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 = $395,731 )
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/19/2023	NON-COMPETING CONTINUATION	$395,731
														Subtotal = $395,731

Issue Date FY: 2023 ( Subtotal = $445,109 )
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/22/2023	NEW	$445,109
														Subtotal = $445,109

Grand Total All Awards = $840,840

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Mutual reinforcement between somatic mutations and transcription factors in clonal hematopoiesis

Award Number: R01DK132286

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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