Interplay between the EMT transcription factors ZEB1 and ZEB2 regulates hematopoietic stem and progenitor cell differentiation and hematopoietic lineage fidelity

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dc.contributor.authorWang, J.
dc.contributor.authorFarkas, C.
dc.contributor.authorBenyoucef, A.
dc.contributor.authorCarmichael, C.
dc.contributor.authorHaigh, K.
dc.contributor.authorWong, N.
dc.contributor.authorHuylebroeck, D.
dc.contributor.authorStemmler, M.P.
dc.contributor.authorBrabletz, S.
dc.contributor.authorBrabletz, T.
dc.contributor.authorNefzger, C.M.
dc.contributor.authorGoossens, S.
dc.contributor.authorBerx, G.
dc.contributor.authorPolo, J.M.
dc.contributor.authorHaigh, J.J.
dc.contributor.editorEaves, C.J.
dc.date.issued2021
dc.descriptionPublished: September 22, 2021
dc.description.abstractThe ZEB2 transcription factor has been demonstrated to play important roles in hematopoiesis and leukemic transformation. ZEB1 is a close family member of ZEB2 but has remained more enigmatic concerning its roles in hematopoiesis. Here, we show using conditional loss-of-function approaches and bone marrow (BM) reconstitution experiments that ZEB1 plays a cell-autonomous role in hematopoietic lineage differentiation, particularly as a positive regulator of monocyte development in addition to its previously reported important role in T-cell differentiation. Analysis of existing single-cell (sc) RNA sequencing (RNA-seq) data of early hematopoiesis has revealed distinctive expression differences between Zeb1 and Zeb2 in hematopoietic stem and progenitor cell (HSPC) differentiation, with Zeb2 being more highly and broadly expressed than Zeb1 except at a key transition point (short-term HSC [ST-HSC]➔MPP1), whereby Zeb1 appears to be the dominantly expressed family member. Inducible genetic inactivation of both Zeb1 and Zeb2 using a tamoxifen-inducible Cre-mediated approach leads to acute BM failure at this transition point with increased long-term and short-term hematopoietic stem cell numbers and an accompanying decrease in all hematopoietic lineage differentiation. Bioinformatics analysis of RNA-seq data has revealed that ZEB2 acts predominantly as a transcriptional repressor involved in restraining mature hematopoietic lineage gene expression programs from being expressed too early in HSPCs. ZEB1 appears to fine-tune this repressive role during hematopoiesis to ensure hematopoietic lineage fidelity. Analysis of Rosa26 locus-based transgenic models has revealed that Zeb1 as well as Zeb2 cDNA-based overexpression within the hematopoietic system can drive extramedullary hematopoiesis/splenomegaly and enhance monocyte development. Finally, inactivation of Zeb2 alone or Zeb1/2 together was found to enhance survival in secondary MLL-AF9 acute myeloid leukemia (AML) models attesting to the oncogenic role of ZEB1/2 in AML.
dc.description.statementofresponsibilityJueqiong Wang, Carlos Farkas, Aissa Benyouce, Catherine Carmichael, Katharina Haigh, Nick Wong, Danny Huylebroeck, Marc P. Stemmler, Simone Brabletz, Thomas Brabletz, Christian M. Nefzger, Steven Goossens, Geert Berx, Jose M. Polo, Jody J. Haigh
dc.identifier.citationPLoS Biology, 2021; 19(9):e3001394-1-e3001394-33
dc.identifier.doi10.1371/journal.pbio.3001394
dc.identifier.issn1544-9173
dc.identifier.issn1545-7885
dc.identifier.orcidPolo, J.M. [0000-0002-2531-778X]
dc.identifier.urihttps://hdl.handle.net/2440/138917
dc.language.isoen
dc.publisherPublic Library of Science (PLoS)
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1104441
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1141081
dc.rights© 2021 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.source.urihttps://doi.org/10.1371/journal.pbio.3001394
dc.subjectBone Marrow Cells
dc.subjectHematopoietic Stem Cells
dc.subjectAnimals
dc.subjectMice, Transgenic
dc.subjectMice
dc.subjectCell Differentiation
dc.subjectHematopoiesis
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectCell Lineage
dc.subjectLeukemia, Myeloid, Acute
dc.subjectZinc Finger E-box-Binding Homeobox 1
dc.subjectZinc Finger E-box Binding Homeobox 2
dc.subjectRNA-Seq
dc.subject.meshBone Marrow Cells
dc.subject.meshHematopoietic Stem Cells
dc.subject.meshAnimals
dc.subject.meshMice, Transgenic
dc.subject.meshMice
dc.subject.meshCell Differentiation
dc.subject.meshHematopoiesis
dc.subject.meshGene Expression Regulation, Neoplastic
dc.subject.meshCell Lineage
dc.subject.meshLeukemia, Myeloid, Acute
dc.subject.meshZinc Finger E-box-Binding Homeobox 1
dc.subject.meshZinc Finger E-box Binding Homeobox 2
dc.subject.meshRNA-Seq
dc.titleInterplay between the EMT transcription factors ZEB1 and ZEB2 regulates hematopoietic stem and progenitor cell differentiation and hematopoietic lineage fidelity
dc.typeJournal article
pubs.publication-statusPublished

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