ORCID ID
Graduation Date
Spring 5-10-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Molecular Genetics & Cell Biology
First Advisor
Kyle J. Hewitt
Abstract
Cellular differentiation which begins with the stem cell and ends with mature cells is guided by various mechanisms like extracellular signals, signal transduction, transcription factor activity, and epigenetic modifications which all influence gene expression to facilitate differentiation. Studies of hematopoietic stem and progenitor cell (HSPC) differentiation have highlighted the intricacy of this process, involving several intermediate states of progressively restricted lineage-committed cells that each require a different set of mechanisms to promote differentiation. Misregulation of differentiation resulting in blocks in differentiation or defective cells cause diseases such as blood cancers, sickle cell anemia, and myelodysplastic syndrome (MDS).
A family of related sterile alpha motif (SAM)-containing proteins have recently been found to coordinate hematopoiesis. The commonly ascribed roles for SAMs in regulating cell signaling and transcription via homo- or heterologous interactions with other SAMs suggest shared control mechanisms. However, in many cases, their function remains uncharacterized. Previously, we identified the sterile alpha motif protein-14 (Samd14) as a coordinator of receptor tyrosine kinase Kit signaling in stress erythropoiesis. Additionally, we identified that the sterile alpha motif protein-1 (SAMD1) protein is expressed highly in hematopoietic stem cells (HSCs) and the erythroid lineage and is predicted to control key hematopoietic transcription factors such as GATA2.
My dissertation research has discovered new functions of Samd14 and SAMD1 in hematopoiesis. Using a conditional Samd14 knockout mouse model, we identified that Samd14 coordinates mast cell differentiation and function through the Kit receptor. It also uncovers new functions of SAMD1 in hematopoiesis. Furthermore, we find that SAMD1 facilitates the output of mature hematopoietic cells. In erythropoiesis, SAMD1 influences the chromatin landscape through coordination of H3K4 methylation. Additionally, with the use of an exciting new human bone marrow organoid model (BMO), SAMD1’s role in HSPCs is examined.
This work identifies new functions of SAM proteins in hematopoiesis. These studies provide a deeper understanding of SAM protein functions in cell biology and identify SAM proteins as coordinators of fundamental differentiation processes.
Recommended Citation
Schaefer, Meg, "Multilineage Hematopoietic Function of SAM-Containing Proteins" (2025). Theses & Dissertations. 914.
https://digitalcommons.unmc.edu/etd/914
Comments
2025 Copyright, the authors