Journal Article

DKFZ-2025-01711

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Lysine-specific demethylase 1 regulates hematopoietic stem cell expansion and myeloid cell differentiation.

Staehle, H. F. ; Koellerer, C. ; Staehle, A. M. ; Schulze, J. ; Eble, P. ; Müller, A. ; Zell, F. ; Müller, J. M. ; Perner, F. ; Attia, A. ; Mallm, J.-P.DKFZ* ; Pozdnyakova, O. ; Rippe, K.DKFZ* ; Brors, B.DKFZ* ; Feuerbach, L.DKFZ* ; Imbusch, C. D.DKFZ* ; Metzger, E. ; Schüle, R. ; Pahl, H. L. ; Jutzi, J. S.

2025
Nature Publishing Group London [u.a.]

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Please use a persistent id in citations: doi:10.1038/s41419-025-07951-z

Abstract: 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.

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Contributing Institute(s):

1. Single-cell Open Lab (W192)
2. B066 Chromatin-Netzwerke (B066)
3. Angewandte Bioinformatik (B330)
4. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

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