Lysine-specific demethylase 1 regulates hematopoietic stem cell expansion and myeloid cell differentiation
The lysine-specific demethylase 1 (LSD1) regulates hematopoietic stem cell differentiation and has been identified as a therapeutic target in hematological disorders. LSD1 demethylates mono and dimethylated histones 3 at lysine 4 and 9. In addition, it acts as a scaffold for the formation of chromatin-modifying complexes that regulates the transcription of myeloid-lineage-specific genes in complex with GFI1, a transcriptional repressor. While both enzymatic and non-enzymatic functions of LSD1 have been well defined, the relative importance of these two functions in hematopoiesis remains incompletely understood. Here, we investigated the contribution of enzymatic and non-enzymatic functions of LSD1 to myelopoiesis. We show that myeloid differentiation is independent of the enzymatic functions of LSD1 but requires the non-enzymatic, scaffolding function, which directs GFI1 binding to target sequences. In the absence of the LSD1 protein, GFI1 DNA binding is diminished, and myeloid cell differentiation arrests at an immature, myelomonocytic-like cell stage, which overexpresses Prtn3. We provide functional data implicating Prtn3 as an effector of the stem cell expansion and myeloid maturation block caused by the loss of LSD1.
Authors
- Lars Feuerbach (ORCID: https://orcid.org/0000-0003-1503-437X)
- Eric Metzger (ORCID: https://orcid.org/0000-0002-1394-1083)
- Christoph Koellerer
- Charles D. Imbusch (ORCID: https://orcid.org/0000-0003-4920-551X)
- Hans Felix Staehle (ORCID: https://orcid.org/0000-0001-5082-0646)
- Heike L. Pahl (ORCID: https://orcid.org/0000-0003-2857-2396)
- Jonas S. Jutzi (ORCID: https://orcid.org/0000-0002-1977-153X)
- Anne Marie Staehle
- Benedikt Brors (ORCID: https://orcid.org/0000-0001-5940-3101)
- Jan‐Philipp Mallm (ORCID: https://orcid.org/0000-0002-7059-4030)
- Franziska Zell
- Karsten Rippe (ORCID: https://orcid.org/0000-0001-9951-9395)
- Aya Attia
- Roland Schüle
- Florian Perner (ORCID: https://orcid.org/0000-0003-1010-3321)
- Olga Pozdnyakova (ORCID: https://orcid.org/0000-0001-8376-0344)
- Judith M. Müller (ORCID: https://orcid.org/0000-0002-7733-3941)
- Anja Müller (ORCID: https://orcid.org/0009-0004-4101-9178)
- Jana Schulze (ORCID: https://orcid.org/0009-0006-1682-4487)
- Philipp Eble
Institutions
- University of Freiburg (DE)
- German Cancer Research Center (DE)
- Johannes Gutenberg University Mainz (DE)
- Heidelberg University (DE)
- Hospital of the University of Pennsylvania (US)
- University Medical Center Freiburg (DE)
- University Hospital Heidelberg (DE)
- Medizinische Hochschule Hannover (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- National Center for Tumor Diseases (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Heidelberg University (US)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2025-08-15
- DOI
- https://doi.org/10.1038/s41419-025-07951-z
- Citations
- 1
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Deutsche Forschungsgemeinschaft
- Albert-Ludwigs-Universität Freiburg
- Else Kröner-Fresenius-Stiftung