Late fetal hematopoietic failure results from ZBTB11 deficiency despite abundant HSC specification
- Author(s)
- Cao, H; Naik, SH; Amann-Zalcenstein, D; Hickey, P; Salim, A; Cao, B; Nilsson, SK; Keightley, MC; Lieschke, GJ;
- Journal Title
- Blood Advances
- Publication Type
- epub ahead of print
- Abstract
- Hematopoiesis produces all the diverse blood cell lineages to meet basal needs and the sudden demands of injury or infection. Rapid response to such challenges requires expansion of specific lineages then prompt return to balanced steady-state levels, necessitating tightly coordinated regulation. We previously identified a requirement for the Zinc finger and BTB-domain containing 11 (ZBTB11) transcription factor in definitive hematopoiesis from a forward genetic screen for zebrafish myeloid mutants. To understand its relevance to mammalian systems, we extended these studies to mouse. When Zbtb11 was deleted in the hematopoietic compartment, embryos died at embryonic day (E) 18.5 with hematopoietic failure. Zbtb11 hematopoietic knockout (Zbtb11hKO) hematopoietic stem cells (HSCs) were overabundantly specified at E14.5 through E17.5 compared to controls. Overspecification was accompanied by loss of stemness, inability to differentiate into committed progenitors and mature lineages in fetal liver, failure to seed fetal bone marrow and total hematopoietic failure. Zbtb11hKO HSCs did not proliferate in vitro and were constrained in cell cycle progression, demonstrating a cell-intrinsic role for Zbtb11 in proliferation and cell cycle regulation in mammalian HSCs. scRNAseq analysis identified Zbtb11-deficient HSCs were underrepresented in an erythroid-primed subpopulation and showed downregulation of oxidative phosphorylation (OXPHOS) pathways and dysregulation of genes associated with the hematopoietic niche. We have identified a cell-intrinsic requirement for Zbtb11-mediated gene regulatory networks in sustaining a pool of maturation-capable hematopoietic stem and progenitor cells.
- Publisher
- ASH
- Research Division(s)
- Immunology; Advanced Technology And Biology
- PubMed ID
- 37567157
- Publisher's Version
- https://doi.org/10.1182/bloodadvances.2022009580
- Open Access at Publisher's Site
https://doi.org/10.1182/bloodadvances.2022009580.- Terms of Use/Rights Notice
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Creation Date: 2023-08-16 02:59:26
Last Modified: 2023-08-16 03:01:19