Sarah M Waldvogel, Virginia Camacho, Dandan Fan, Anna Guzman, Alejandra Garcia-Martell, Elmira Khabusheva, Jacey Rodriguez Pridgen, Josephine De La Fuente, Rachel E Rau, Ashlyn Laidman, Maria N Barrachina, Estelle Carminita, Justin Andrew Courson, Michael Williamson, Joanne Ino Hsu, Chun-Wei Chen, Jaime Reyes, Subhashree Pradhan, Rolando Rumbaut, Alan Burns, Benjamin Deneen, Jianzhong Su, Kellie R Machlus, Margaret A Goodell
Author Information
Sarah M Waldvogel: Baylor College of Medicine, Houston, Texas, United States.
Virginia Camacho: Boston Childrens Hospital, Boston, Massachusetts, United States.
Dandan Fan: Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, China.
Anna Guzman: Baylor College of Medicine, Houston, Texas, United States.
Alejandra Garcia-Martell: Baylor College of Medicine, Houston, Texas, United States.
Elmira Khabusheva: Baylor College of Medicine, Houston, Texas, United States.
Jacey Rodriguez Pridgen: Baylor College of Medicine, Houston, Texas, United States. ORCID
Josephine De La Fuente: Baylor College of Medicine, Houston, Texas, United States.
Rachel E Rau: Baylor College of Medicine, United States. ORCID
Ashlyn Laidman: Baylor College of Medicine, Houston, Texas, United States. ORCID
Maria N Barrachina: Boston Children's Hospital, Boston, Massachusetts, United States.
Estelle Carminita: Boston Childrens Hospital, Boston, Massachusetts, United States. ORCID
Justin Andrew Courson: Michael E Debakey VA Medical Center, United States. ORCID
Michael Williamson: Baylor College of Medicine, Houston, Texas, United States. ORCID
Joanne Ino Hsu: Dana Farber Cancer Institute, Boston, Massachusetts, United States.
Chun-Wei Chen: Baylor College of Medicine, Houston, Texas, United States. ORCID
Jaime Reyes: Baylor College of Medicine, Houston, Texas, United States. ORCID
Subhashree Pradhan: Baylor College of Medicine.
Rolando Rumbaut: Baylor College of Medicine, United States. ORCID
Alan Burns: University of Houston, Houston, Texas, United States.
Benjamin Deneen: Baylor College of Medicine, Houston, Texas, United States.
Jianzhong Su: Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, China.
Kellie R Machlus: Harvard Medical School and Boston Children's Hospital, Boston, Massachusetts, United States. ORCID
Margaret A Goodell: Baylor College of Medicine, Houston, Texas, United States. ORCID
Hematopoietic stem cells (HSCs) are defined by their capacity to regenerate all main components of the peripheral blood, but individual HSCs exhibit a range of preferences for generating downstream cell types. Their propensities are thought to be epigenetically encoded, but few differential regulatory mechanisms have been identified. In this work, we explored the role of the DNA methyltransferase 3A (DNMT3A) in the megakaryocyte-biased HSC population, which is thought to reside at the top of the hematopoietic hierarchy. We demonstrate that heterozygous loss of DNMT3A (Dnmt3a+/-) in these megakaryocyte-biased HSCs has consequences distinct from the rest of the HSC pool. These megakaryocyte-biased HSCs become delayed in their lymphoid-repopulating ability but can ultimately regenerate all lineages. We further demonstrate that Dnmt3a+/- mice have increased numbers of megakaryocytes in the bone marrow. Analysis of DNA methylation differences between WT and Dnmt3a+/- HSC subsets, megakaryocyte-erythroid progenitors (MEP), and megakaryocytes revealed that DNA methylation is eroded in the mutants in a cell type-specific fashion. While transcriptional differences between the WT and Dnmt3a+/- megakaryocyte-biased HSCs are subtle, the pattern of DNA methylation loss in this HSC subset is almost completely different from that in non-megakaryocyte-biased HSCs. Together, our findings establish the role of epigenetic regulation in the fate of megakaryocyte-biased HSCs and their downstream progeny and suggest that the outcomes of DNMT3A loss might vary depending on the identity of the HSC that acquires the mutation.
