Helen Wang

Program: Molecular Genetics and Genomics

Current advisor: Jeffrey Magee, MD, PhD

Undergraduate university: Mount Holyoke College, 2018

Enrollment year: 2020

Research summary
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.

Graduate publications
Mendoza-Castrejon J, Yang W, Denby ED, Wang HC, Casey EB, Muthukumar R, Patel RM, Yoon J, Li Y, White JM, Chen R, Batista LFZ, Magee JA. 2025 Fetal context conveys heritable protection against MLL-rearranged AML that depends on MLL3. Blood, 147(1):61-72. PMCID: PMC12758594

Wang HC, Chen R, Yang W, Li Y, Muthukumar R, Patel RM, Casey EB, Denby E, Magee JA. 2024 Kmt2c restricts G-CSF-driven HSC mobilization and granulocyte production in a methyltransferase-independent manner. Cell Rep, 43(8):114542. PMCID: PMC11423277

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