Role of UTX in the regulation of hematopoietic stem cell fate decisions during cell cycle progression.

• Applicant: Professor Dr. Ben Wielockx, Ph.D., since 10/2023
• Subject Area: Cell Biology ; Hematology, Oncology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 464835070

Hematopoietic stem cells (HSCs) produce all blood cells throughout the entire life of an individual. HSCs can divide in three ways: symmetrically - leading to two stem cells (self-renewal) or two differentiated cells, and asymmetrically (give rise to one stem cell and one differentiating progenitor). The process that coordinates this HSC fate decision is critically important. It ensures a balanced blood production during steady-state and upon hematological stress. Dysregulation of this process can result in malignant transformation or bone marrow failure syndromes. In an extended set of preliminary experiments, we found that HSCs could already make differentiation decisions in the G1 phase of the cell cycle. Our results reveal that in this phase, HSCs contain the lowest level of H3K27me3. Therefore, we hypothesize that the functionality of UTX (specific H3K27me3 histone de-methylase) coordinates HSCs fate decisions during G1 phase. With this project, we propose to study the mechanisms underlying the HSC fate decision and its dysregulation, using a unique UTX-deletion mouse model, including a reporter to follow HSC cell cycle progression in vivo. We will analyze chromatin accessibility and histone modifications for different transcription factors responsible for HSC differentiation and self-renewal during cell cycle progression. Our research will help to understand how HSCs regulate their fate in different circumstances and potentially help to develop new anti-tumor therapies.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Dr. Tatyana Grinenko, until 9/2023