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A Myt1 family transcription factor defines neuronal fate by repressing non-neuronal genes

ABSTRACT: Cellular differentiation requires both activation of target cell programs and repression of non-target cell programs. Transcriptional repressors such as RE1-silencing transcription factor (REST) and Hairy/Enhancer of Split (Hes) repress neuronal genes in non-neuronal cells. However, it is unknown whether transcriptional repressors of non-neuronal genes in neuronal precursors are required to specify neuronal fate during development. The Myt1 family of zinc finger transcription factors contributes to fibroblast to neuron reprogramming in vitro by repressing Notch signaling. Here, we show that ztf-11 (Zinc-finger Transcription Factor-11), the sole Caenorhabditis elegans Myt1 homolog, is required for neurogenesis in multiple neuronal lineages, including an in vivo developmental epithelial-to-neuronal transdifferentiation event. ztf-11 is exclusively expressed in all neuronal precursors with remarkable specificity at single cell resolution. Loss of ztf-11 leads to upregulation of non-neuronal genes and reduced neurogenesis. Ectopic expression of ztf-11 in epidermal lineages is sufficient to produce additional neurons. Our genetic and genomic experiments show that ZTF-11 indeed functions as a transcriptional repressor to suppress the activation of non-neuronal genes in neurons; however, it does not function via repression of Notch signaling. Instead, ZTF-11 binds to the MuvBco-repressor complex, which we show is also required for neurogenesis. These results dovetail with ability of Myt1l (Myt1-like) to drive neuronal transdifferentiation in vitro in vertebrate systems. Together, we identified an evolutionarily conserved mechanism to specify neuronal cell fate by repressing non-neuronal genes.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE125694 | GEO | 2019/01/26

REPOSITORIES: GEO

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Project description:Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs. In reprogramming, the same factors are often used to reprogram many different donor cell types. As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors, it remains unclear how identical combinations of transcription factors can silence so many different donor programs. Distinct lineage repressors would have to be induced in different donor cell types. Here we found that the pan neuron-specific transcription factor Myt1-like (Myt1l) exerts its pro-neuronal function by direct repression of many different somatic lineage programs but not the neuronal program during reprogramming and neurogenesis and in primary mouse neurons. The repressive function of Myt1l is mediated by recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. In agreement with its repressive function, the genomic binding sites of Myt1l are similar in neurons and fibroblasts and are preferentially in an open chromatin configuration. The Notch signalling pathway is repressed by Myt1l through silencing of several members, including Hes1. Acute knock-down of Myt1l in the developing mouse brain mimicked a Notch gain-of-function phenotype, suggesting that Myt1l allows newborn neurons to escape Notch activation during normal development. Depletion of Myt1l in primary postmitotic neurons de-repressed non-neuronal programs and impaired neuronal gene expression and function, indicating that many somatic lineage programs are actively and persistently repressed by Myt1l to maintain neuronal identity. It is now tempting to speculate that similar ‘many-but-one’ lineage repressors exist for other cell fates; such repressors, in combination with lineage-specific activators, would be prime candidates for use in reprogramming additional cell types.

Project description:modENCODE_submission_4626 This submission comes from a modENCODE project of Michael Snyder. For full list of modENCODE projects, see http://www.genome.gov/26524648 Project Goal: We are identifying the DNA binding sites for 300 transcription factors in C. elegans. Each transcription factor gene is tagged with the same GFP fusion protein, permitting validation of the gene's correct spatio-temporal expression pattern in transgenic animals. Chromatin immunoprecipitation on each strain is peformed using an anti-GFP antibody, and any bound DNA is deep-sequenced using Solexa GA2 technology. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf EXPERIMENT TYPE: CHIP-seq. BIOLOGICAL SOURCE: Strain: OP236(official name : OP236 genotype : unc119(ed3);wgIs236(elk-2::TY1 EGFP FLAG;unc119) outcross : 3 mutagen : Bombard tags : GFP::3xFlag description : This strain's transgene was constructed by Mihail Sarov at the Max Planck Institute for Cell Biology in Tubiginen using Tony Hyman's recombineering pipeline. The resulting plasmid was used for biolistic transformation of an unc-119(ed3) strain. The ZTF-11::EGFP fusion protein is expressed in the correct ztf-11 spatio-temporal expression pattern. This strain was used for ChIP-seq experiments to map the in vivo binding sites for the ZTF-11 transcription factor. made_by : Unknown ); Developmental Stage: L3; Genotype: unc119(ed3);wgIs236(elk-2::TY1 EGFP FLAG;unc119); Sex: Hermaphrodite; EXPERIMENTAL FACTORS: Developmental Stage L3; Target gene ztf-11; Strain OP236(official name : OP236 genotype : unc119(ed3);wgIs236(elk-2::TY1 EGFP FLAG;unc119) outcross : 3 mutagen : Bombard tags : GFP::3xFlag description : This strain's transgene was constructed by Mihail Sarov at the Max Planck Institute for Cell Biology in Tubiginen using Tony Hyman's recombineering pipeline. The resulting plasmid was used for biolistic transformation of an unc-119(ed3) strain. The ZTF-11::EGFP fusion protein is expressed in the correct ztf-11 spatio-temporal expression pattern. This strain was used for ChIP-seq experiments to map the in vivo binding sites for the ZTF-11 transcription factor. made_by : Unknown ); temp (temperature) 20 degree celsius

Project description:modENCODE_submission_4627 This submission comes from a modENCODE project of Michael Snyder. For full list of modENCODE projects, see http://www.genome.gov/26524648 Project Goal: We are identifying the DNA binding sites for 300 transcription factors in C. elegans. Each transcription factor gene is tagged with the same GFP fusion protein, permitting validation of the gene's correct spatio-temporal expression pattern in transgenic animals. Chromatin immunoprecipitation on each strain is peformed using an anti-GFP antibody, and any bound DNA is deep-sequenced using Solexa GA2 technology. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf EXPERIMENT TYPE: CHIP-seq. BIOLOGICAL SOURCE: Strain: OP236(official name : OP236 genotype : unc119(ed3);wgIs236(elk-2::TY1 EGFP FLAG;unc119) outcross : 3 mutagen : Bombard tags : GFP::3xFlag description : This strain's transgene was constructed by Mihail Sarov at the Max Planck Institute for Cell Biology in Tubiginen using Tony Hyman's recombineering pipeline. The resulting plasmid was used for biolistic transformation of an unc-119(ed3) strain. The ZTF-11::EGFP fusion protein is expressed in the correct ztf-11 spatio-temporal expression pattern. This strain was used for ChIP-seq experiments to map the in vivo binding sites for the ZTF-11 transcription factor. made_by : Unknown ); Developmental Stage: L4; Genotype: unc119(ed3);wgIs236(elk-2::TY1 EGFP FLAG;unc119); Sex: Hermaphrodite; EXPERIMENTAL FACTORS: Developmental Stage L4; Target gene ztf-11; Strain OP236(official name : OP236 genotype : unc119(ed3);wgIs236(elk-2::TY1 EGFP FLAG;unc119) outcross : 3 mutagen : Bombard tags : GFP::3xFlag description : This strain's transgene was constructed by Mihail Sarov at the Max Planck Institute for Cell Biology in Tubiginen using Tony Hyman's recombineering pipeline. The resulting plasmid was used for biolistic transformation of an unc-119(ed3) strain. The ZTF-11::EGFP fusion protein is expressed in the correct ztf-11 spatio-temporal expression pattern. This strain was used for ChIP-seq experiments to map the in vivo binding sites for the ZTF-11 transcription factor. made_by : Unknown ); temp (temperature) 20 degree celsius

Project description:modENCODE_submission_4791 This submission comes from a modENCODE project of Michael Snyder. For full list of modENCODE projects, see http://www.genome.gov/26524648 Project Goal: We are identifying the DNA binding sites for 300 transcription factors in C. elegans. Each transcription factor gene is tagged with the same GFP fusion protein, permitting validation of the gene's correct spatio-temporal expression pattern in transgenic animals. Chromatin immunoprecipitation on each strain is peformed using an anti-GFP antibody, and any bound DNA is deep-sequenced using Solexa GA2 technology. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf EXPERIMENT TYPE: CHIP-seq. BIOLOGICAL SOURCE: Strain: OP236(official name : OP236 genotype : unc-119(ed3) III; wgIs236(ekl-2::TY1 EGFP FLAG; unc-119(+)) outcross : 3 mutagen : Bombard tags : GFP::3xFlag description : This strain's transgene was constructed by Mihail Sarov at the Max Planck Institute for Cell Biology and Genetics in Dresden description : using Tony Hyman's recombineering pipeline. The resulting plasmid was used for biolistic transformation of an unc-119(ed3) strain. The ZTF-11::EGFP fusion protein is expressed in the correct ztf-11 spatio-temporal expression pattern. This strain was used for ChIP-seq experiments to map the in vivo binding sites for the ZTF-11 transcription factor. made_by : Unknown ); Developmental Stage: embryo; Genotype: unc-119(ed3) III; wgIs236(ekl-2::TY1 EGFP FLAG; unc-119(+)); Sex: mixed Male and Hermaphrodite population; EXPERIMENTAL FACTORS: Developmental Stage embryo; Target gene ztf-11; Strain OP236(official name : OP236 genotype : unc-119(ed3) III; wgIs236(ekl-2::TY1 EGFP FLAG; unc-119(+)) outcross : 3 mutagen : Bombard tags : GFP::3xFlag description : This strain's transgene was constructed by Mihail Sarov at the Max Planck Institute for Cell Biology and Genetics in Dresden description : using Tony Hyman's recombineering pipeline. The resulting plasmid was used for biolistic transformation of an unc-119(ed3) strain. The ZTF-11::EGFP fusion protein is expressed in the correct ztf-11 spatio-temporal expression pattern. This strain was used for ChIP-seq experiments to map the in vivo binding sites for the ZTF-11 transcription factor. made_by : Unknown ); temp (temperature) 20 degree celsius

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A Myt1 family transcription factor defines neuronal fate by repressing non-neuronal genes

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