Zeb2 DNA-Binding Sites in Neuroprogenitor Cells Reveal Autoregulation and Affirm Neurodevelopmental Defects, Including in Mowat-Wilson Syndrome
| Autor: | Judith C. Birkhoff, Anne L. Korporaal, Rutger W. W. Brouwer, Karol Nowosad, Claudia Milazzo, Lidia Mouratidou, Mirjam C. G. N. van den Hout, Wilfred F. J. van IJcken, Danny Huylebroeck, Andrea Conidi |
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| Rok vydání: | 2023 |
| Předmět: |
NEURONAL DIFFERENTIATION
neural differentiation Biology Cell fate determination Transcriptome transcriptomics CONDITIONAL KNOCKOUT syndromes chromatin immunoprecipitation sequencing Genetics Zeb2 Mowat-Wilson syndrome PITT-HOPKINS-SYNDROME Transcription factor Gene knockout transcription factor Genetics (clinical) Genetics & Heredity Science & Technology SMAD-INTERACTING PROTEIN-1 Neurogenesis HIRSCHSPRUNG-DISEASE embryonic stem cells Embryonic stem cell neurodevelopmental disorder target genes EPITHELIAL-MESENCHYMAL TRANSITION NERVOUS-SYSTEM Cell biology DNA binding site TRANSCRIPTION FACTORS Knockout mouse SIP1 Life Sciences & Biomedicine MENTAL-RETARDATION |
| Zdroj: | Genes Volume 14 Issue 3 Pages: 629 |
| ISSN: | 2073-4425 |
| DOI: | 10.3390/genes14030629 |
| Popis: | Perturbation and mechanistic studies have shown that the DNA-binding transcription factor Zeb2 controls cell fate decision, differentiation and/or maturation in multiple cell lineages in embryos and after birth. In cultured embryonic stem cells (ESCs) Zeb2s strong upregulation is necessary for their exit from primed pluripotency and entering neural and general differentiation. We engineered mouse ESCs to produce epitope-tagged Zeb2 from one of its two endogenous alleles. Using crosslinking ChIP-sequencing, we mapped for the first time 2,432 DNA-binding sites of Zeb2 in ESC-derived neuroprogenitor cells (NPCs). A new, major site maps promoter-proximal to Zeb2 itself, and its homozygous removal demonstrates that Zeb2 autoregulation is necessary to elicit proper Zeb2 effects in ESC[->]NPC differentiation. We then cross-referenced all Zeb2 DNA-binding sites with transcriptome data from Zeb2 perturbations in ESCs, ventral forebrain in mouse embryos, and adult neurogenesis. While the characteristics of these neurodevelopmental systems differ, we find interesting overlaps. Collectively, these new results obtained in ESC-derived NPCs significantly add to Zeb2s role as neurodevelopmental regulator as well as the causal gene in Mowat-Wilson Syndrome. Also, Zeb2 was found to map to loci mutated in other human congenital syndromes, making variant or disturbed levels of ZEB2 a candidate modifier principle in these. Significance statementZeb2 is needed for exit from primed pluripotency and differentiation of ESCs and being studied in various cell lineages and tissues/organs in knockouts and adult mice. Phenotyping has mainly documented transcriptomes of Zeb2-mutant affected cell types, but ChIP-seq data are still not available to document Zeb2s direct target loci as repressor or activator of transcription. This study maps for the first time the Zeb2 genome-wide binding sites in ESC-derived neuroprogenitors, and discovered Zeb2 autoregulation. Cross-referencing these ChIP-seq data with transcriptome profiles of Zeb2 perturbation further explains Mowat-Wilson Syndrome defects and proposes ZEB2 as candidate modifier gene in other syndromes. |
| Databáze: | OpenAIRE |
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