# The role of Kmt2c/MLL3 in hematopoietic stem cell self-renewal, commitment and exhaustion > **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $475,499 ## Abstract PROJECT SUMMARY The overarching goal of this proposal is to understand how two highly homologous epigenetic regulators, MLL3 and MLL4, coordinate critical cell fate decisions during adult blood development. Considerable prior work has gone into understanding the transcription factor networks that coordinate blood development, particularly at the level of hematopoietic stem cells (HSCs), multipotent progenitors (MPPs), and lineage committed progenitors. These networks are important because they maintain blood and immune system homeostasis, and they touch on essentially every human blood disorder. Like transcription factors, epigenetic regulators are also critical for blood development and homeostasis, as evidenced by the fact that they are frequently mutated in clonal hematopoiesis and various leukemias. However, unlike transcription factors – which often have well- characterized DNA binding motifs, binding partners, and cis-regulatory elements – we currently have only limited insight into how epigenetic regulators are deployed to effect specific cell fate decisions. The case of MLL3 and MLL4 illustrates both the importance of epigenetic regulation in blood development and our limited understanding of their underlying mechanisms. MLL3 and MLL4 each nucleate a multiprotein, chromatin-bound complex called the Complex of Proteins Associated with SET1(COMPASS). MLL3 and MLL4 are highly homologous, and both bind enhancer elements to promote gene expression. However, the proteins have very distinct functions in HSCs and MPPs despite their shared homology. MLL4 maintains HSC self-renewal capacity while opposing myeloid differentiation, whereas MLL3 antagonizes HSC self-renewal while promoting differentiation. These observations create a unique opportunity to learn how structurally similar epigenetic regulators can be selectively recruited to discrete cis-regulatory elements to convey specific hematopoietic fates. In new preliminary studies, we made additional discoveries that shape the aims of this proposal. Specifically, we discovered that MLL3 and MLL4 have redundant roles in licensing HSC identity and myeloid potential despite their apparently antagonistic functions. Inactivating both proteins causes HSCs/MPPs to adopt a B-lymphoid primed state. We propose the following two aims to investigate the underlying causes of these cell fate changes. Aim 1 is to define mechanisms by which MLL3 and MLL4 license HSC identity, as well as mechanisms that account for their distinct functions in HSC self-renewal and differentiation. Aim 2 is to define MLL3/4 COMPASS- independent mechanisms of B-lymphoid development. We will use a combination of genetically engineered mice and various genomic and proteomic techniques to identify cis-regulatory elements, transcription factors and chromatin binding proteins that mediate MLL3- and MLL4-specific cell fates. In each aim, we will focus on understanding the regulatory logic that defines MLL3/4 COMPASS usage or COMPASS inde... ## Key facts - **NIH application ID:** 10878420 - **Project number:** 2R01HL152180-05 - **Recipient organization:** WASHINGTON UNIVERSITY - **Principal Investigator:** Jeffrey Alan Magee - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $475,499 - **Award type:** 2 - **Project period:** 2020-04-01 → 2028-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10878420 ## Citation > US National Institutes of Health, RePORTER application 10878420, The role of Kmt2c/MLL3 in hematopoietic stem cell self-renewal, commitment and exhaustion (2R01HL152180-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10878420. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*