Dissecting the functions of EBF1 in haematopoietic progenitors and on T lymphopoiesis

Abstract: Haematopoietic stem cells (HSC) and multipotent progenitors (MPP) generate all cells of the blood system, and haematopoietic differentiation can be influenced by intrinsic factors, such as lineage-specifying transcription factors, and extrinsic cues, such as lineage-instructive cytokines or cell-cell contact with the bone marrow (BM) niche. The BM niche is formed by multiple non-haematopoietic cells, such as mesenchymal stromal cells and endothelial cells, and play a crucial role in maintaining HSC quiescence and directing cell differentiation. Comparably, T cell development and tolerance is strongly dependent on interactions with the thymus microenvironment. In recent years, we have come to appreciate the heterogeneity of MPPs, which are further defined by their lineage potentials; MPP2 differentiate preferentially towards erythroid and megakaryocytic lineages, MPP3 towards myeloid lineages and MPP4 towards lymphoid lineages. Despite their multipotency, MPPs display poorly understood lineage bias, prompting us to revisit the role of lineage-specifying transcription factors in lineage specification. Transcription factor Early B cell factor 1 (EBF1) orchestrates the B cell lineage program and is essential for B cell commitment. The B cell transcriptional network in which EBF1 acts has been extensively studied, however, at which point along haematopoietic differentiation does EBF1 initiate its function remains to be elucidated. Furthermore, EBF1 is expressed and plays a role in a number of non-haematopoietic cell types such as stromal cells. It was previously shown that EBF1 plays a role in BM mesenchymal stem cells, in influencing the adhesion of HSCs, and subsequently their self-renewal capacity. This led us to question whether EBF1 influences haematopoiesis via other non-haematopoietic cell types.
First, we examined whether B-lineage determinant EBF1, regulates lineage preference in haematopoietic progenitors. We detected low level EBF1 expression in myeloid-biased MPP3 and lymphoid-biased MPP4 cells, coinciding with expression of the myeloid determinant C/EBPα. Hematopoietic deletion of Ebf1 results in enhanced myelopoiesis and reduced HSC repopulation capacity. Ebf1-deficient MPP3 and MPP4 cells exhibit augmented myeloid differentiation potential and a myeloid-enriched transcriptome that is inversely correlated with Cebpa-deficient progenitors. Correspondingly, EBF1 binds the Cebpa enhancer and Ebf1-deficient MPP3 and MPP4 cells upregulate Cebpa expression. In addition, EBF1 primes the chromatin of B-lymphoid enhancers specifically in MPP3 cells. Thus, our study implicates EBF1 in regulating myeloid/lymphoid fate bias in MPPs by constraining C/EBPα-driven myelopoiesis and priming the B-lymphoid fate.
Secondly, we explored whether EBF1 expression in thymic stromal cells influences T lymphopoiesis. We detected specific EBF1 expression in thymic endothelial cells (ECs), and endothelial deletion of Ebf1 results in a reduction of the early thymic progenitors. Lymphoid progenitors in the BM and T cell development in the thymus exhibited no defect upon Ebf1 deletion. Transcriptome analysis of thymic ECs revealed a strong upregulation of Claudin-5 expression upon Ebf1 deletion, resulting in decreased permeability of the blood-thymus-barrier. In this thesis, we have identified vital functions of EBF1 in the regulation of haematopoiesis, through the regulation of lineage specification in MPPs, and through the regulation of blood-thymus-barrier in thymic endothelial cells

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Universität Freiburg, Dissertation, 2022

Klassifikation und Themen

• Schlagwort: Zelldifferenzierung ; Blutstammzelle ; Vorläuferzelle ; Transkriptionsfaktor ; Onkoproteine ; T-Lymphozyt

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2022
• Urheber: Lenaerts, Aurelie
• Beteiligte Personen und Organisationen: Grosschedl, Rudolf ; Cabezas Wallscheid, Nina ; Börries, Melanie ; Albert-Ludwigs-Universität Freiburg. Fakultät für Biologie

Weitere Informationen

• DOI: 10.6094/UNIFR/225726
• URN: urn:nbn:de:bsz:25-freidok-2257262
• Rechteinformation: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 14.08.2025, 10:49 MESZ