Examining the impact of DNMT3A protein reduction on normal and clonal hematopoiesis

The National Heart, Lung, and Blood Institute awarded Baylor College of Medicine $158,892 on September 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to examine the impact of DNMT3A protein reduction on normal and clonal hematopoiesis.

The research investigates mechanisms by which somatic DNMT3A mutations drive clonal hematopoiesis—the clonal expansion of mutated hematopoietic stem and progenitor cells—which accelerates with age and increases the risk of hematologic disorders including aplastic anemia and myelodysplastic syndrome, as well as chronic inflammatory diseases such as cardiovascular disease and increased all-cause mortality. Dr. Taishi Yonezawa will characterize USP11-dependent mechanisms controlling DNMT3A protein fate in hematopoiesis during the K99 phase and identify approaches to modulate clonal hematopoiesis caused by unstable DNMT3A using DCAF8 knockout mice during the R00 phase. The investigation employs CRISPR screening, mass spectrometry, and a genetically engineered mouse model to uncover mechanisms of DNMT3A protein turnover and prevent protein loss in clonal hematopoiesis.

Performance will occur in Houston, Texas, from September 1, 2026, through July 31, 2028. This is a Project Grant, classified as assistance funding to a private nonprofit research-intensive academic health sciences institution.

Abstract

And abstract certain somatic mutations result in the clonal expansion of mutated hematopoietic stem and progenitor cells (hspcs). This phenomenon, called clonal hematopoiesis (CH), accelerates with age and is associated with an ~11-fold increase in the risk of hematologic disorders such as aplastic anemia (AA) and myelodysplastic syndrome (MDS), as well as chronic inflammatory diseases like cardiovascular disease, and increased all-cause mortality. DNA methyltransferase 3A (DNMT3A) plays an important role in regulating normal hspc proliferation, and mutations in DNMT3A are some of the most common in CH. Our recent research shows that one-third of CH-related mutations in DNMT3A downregulate its protein levels through the E3 ubiquitin ligase adaptor DCAF8 in hematopoiesis, and this effect is counteracted by the deubiquitinating enzyme USP11. As a result of these mutations, the DNA mtase activity of DNMT3A is decreased in mutant hematopoietic cells. DR. Taishi yonezawa hypothesizes that maintaining wild-type (WT) levels of DNMT3A protein is critical for normal hematopoiesis and the disruption of DNMT3A protein function leads to CH. To address his hypothesis, he will investigate the mechanisms underlying the regulation of DNMT3A WT protein fate in hematopoiesis (K99 phase) and identify approaches to modulate CH caused by unstable DNMT3A using DCAF8 KO mice (R00 phase). Overall, improving our understanding of DNMT3A protein function will shed light on how IT regulates normal hspc proliferation and hematopoiesis, and how its disruption contributes to CH. In this proposal, DR. Yonezawa aims to fill this critical GAP in knowledge and uncover the mechanisms of DNMT3A protein turnover to prevent its protein loss in CH using crispr screening, mass spectrometry, and a genetically engineered mouse model. Specifically, he will (1) characterize USP11-dependent mechanisms controlling DNMT3A protein fate (K99), and (2) determine the effects of DCAF8 on DNMT3A protein turnover in vivo (R00). This work will advance our understanding of normal hematopoiesis and CH and reveal mechanisms underlying DNMT3A protein regulation. If successful, this proposal could open new avenues to modulate and prevent CH. DR. Yonezawa is a postdoctoral fellow at baylor college of medicine (BCM). His expertise includes computer science, protein engineering, molecular biology, and physiology with a focus on elucidating CH. His long-term goal is to elucidate the molecular mechanisms and protein-level regulation underlying hematopoiesis to modulate CH. The proposed research will provide new training for him in the fields of hspcs and CH. The K99 phase work will be performed at BCM, a stellar research environment with cutting-edge facilities. DR. Margaret (peggy) goodell - a leading expert on DNMT3A in normal and malignant hematopoiesis who has received numerous awards for her mentorship of promising young scientists - will serve as his mentor. Under her guidance and through his thoughtful career development plan, DR. Yonezawa is well positioned to establish an independent research lab and become a leader himself in the field of normal and clonal hematopoiesis.