Li, Jin: Zeb2 is essential for terminal differentiation of multiple hematopoietic lineages. - Bonn, 2016. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5n-42610
@phdthesis{handle:20.500.11811/6711,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5n-42610,
author = {{Jin Li}},
title = {Zeb2 is essential for terminal differentiation of multiple hematopoietic lineages},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2016,
month = jan,

note = {The differentiation of hematopoietic stem cells (HSC) into specialized blood cells is tightly controlled by a complex network of transcription factors (TF). The zinc finger E-Box binding TF Zeb2 is known to govern the epithelial to mesenchymal transition (EMT) during embryonic development and tumor progression and metastasis in an adult organism. Our previous work showed that deletion of Zeb2 within hematopoietic compartment resulted in early embryonic lethality due to differentiation and migration defects. In order to identify the role of Zeb2 in adult hematopoiesis, the Mx1-Cre based inducible Zeb2 knockout model was used. We found drastic reduction of B-lymphocytes, monocytes, platelets and erythrocytes in peripheral blood while accumulation of hematopoietic stem and progenitor cells in the bone marrow after Zeb2 deletion.
In this study, we firstly demonstrated that impaired terminal differentiation of the erythroid lineage takes place at the transition of CD71highTER119+ to CD71medTER119+ population upon Zeb2 ablation. This may be caused by the dysregulation of several transcription regulators, including Klf1 and Fli1 and Gata1. In addition, the most prominent differentiation block was observed within B lymphopoiesis at the Prepro-B to Pro-B cell transition. The early B-cell receptor IL-7R as well as fingerprint transcription factors such as Runx1, E2A, EBF1 and Pax5 were markedly changed in Zeb2Δ/ΔMx1-Cre Prepro-B cells. Moreover, the expression level of DNA methylation related genes and histone modifications were significantly changed in Zeb-deficient early B-cells, suggesting the B-cell differentiation block due to altered epigenetic regulation.
A set of higher or lower methylated key HSC genes were discovered by reduced representation bisulfite sequencing (RRBS) analysis between Zeb2 WT and Zeb2Δ/ΔMx1-Cre HSCs. Gene ontology (GO) enrichment analysis highlights altered protein kinases (including phosphorylation, Serine/threonine protein kinase, tyrosine protein kinase) after Zeb2 deletion. This was further confirmed by abnormal JAK/STAT activity in Zeb2Δ/ΔMx1-Cre cells.
In summary, Zeb2 is essential for multilineage differentiation at different stages of hematopoiesis. Ablation of Zeb2 in adult hematopoiesis results in defective epigenetic regulation, a causative event in impaired transcriptional network and JAK/STAT activation that account for multilineage defects.},

url = {http://hdl.handle.net/20.500.11811/6711}
}

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