MSTP in PhD Training
Program: Molecular Genetics and Genomics
Current advisor: Jeffrey Magee, MD, PhD
Undergraduate university: Mount Holyoke College, 2018
Enrollment year: 2020
Defining Distinct and Redundant Roles of MLL3 and MLL4 in Hematopoietic Stem Cell Self-Renewal and Differentiation
Kmt2c and Kmt2d are homologous genes that govern cell fate decisions in embryonic and tissue-specific stem cells. They encode MLL3 and MLL4, respectively, each nucleating a COMPASS (complex of proteins associated with Set1). MLL3 and MLL4 monomethylate Histone H3, Lysine 4 residues at enhancers for transcriptional activation. They can reinforce recruitment of transcriptional coactivators while antagonizing repressors. Despite extensive studies on the functions of MLL3/MLL4-COMPASS complexes in pluripotent embryonic stem cells (ESCs), little is known about their roles in multipotent somatic stem cells. As a well-characterized system, hematopoietic stem cells (HSCs) offer a window to study the role of MLL3 and MLL4 in somatic stem cell self-renewal and fate specification.
Interestingly, Kmt2c and Kmt2d loss-of-function mutations have been reported with contrasting phenotypes in hematopoiesis. Kmt2d loss impairs HSC self-renewal and enhances myeloid differentiation at the expense of lymphopoiesis, whereas Kmt2c deletions enhance HSC self-renewal and impair differentiation. Given the structural similarities of MLL3 and MLL4, it is unclear whether they are solely antagonistic or partially redundant in hematopoiesis. Through functional and genomic studies, I plan to define the distinct and redundant roles of MLL3 and MLL4 in HSC self-renewal and hematopoietic differentiation.
Li Y, Yang W, Wang HC, Patel RM, Casey EB, Denby E, Magee JA. 2023 Basal type I interferon signaling has only modest effects on neonatal and juvenile hematopoiesis. Blood Adv, 7(11):2609-2621. PMCID: PMC10250919