Similar Datasets
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.
2017-04-05 | GSE72121 | GEO
Project description:Here we performed a ChIP-seq experiment on a sample of adherent cultures of mouse neural stem cells (NS5 cell line) expressing an inducible HA-tagged version of the proneural factor MyT1 (MyT1-HA, under TetON control) after activation by doxycycline hyclate (DOX). This resulted in the generation of a genome-wide map of MyT1-HA binding to chromatin.
2016-09-09 | E-MTAB-4330 | biostudies-arrayexpress
Project description: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.
2019-01-26 | GSE125694 | GEO
Project description:After performing an in-vivo screening with U87 glioblastoma cells transduced with a knockdown library several genes could be identified. Lin7a which was one of the candidates was further evaluated. Single knockdown of Lin7a in U87 conferred a pro-invasive phenotype in-vitro and in-vivo. Overexpression of Lin7a in the Primary glioblastoma cell line T269 reduced its invasive phenotype. To decipher the underlying pathways U87 control, U87-shLIN7a and U87-shLin7a+Lin7A (rescue cells after re-expression of Lin7A) were analyzed after in-vitro culture by a transcription profiling Array.
2017-08-27 | E-MTAB-5871 | biostudies-arrayexpress
Project description:Here we performed a microarray experiment on samples of adherent cultures of mouse neural stem cells (NS5 cell line) expressing an inducible version of the transcription factor MyT1 (MyT1-V5 TetON) under normal growth conditions and after 4 hours of treatment by doxycyline. This resulted in the generation of a genome-wide mRNA expression pattern and quantification for these cells in the two conditions.
2016-09-09 | E-MTAB-4335 | biostudies-arrayexpress
Project description:MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life. How MYT1L mutations cause neurological phenotypes and whether they can be targeted remains enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients. MYT1L target genes, including WNT and NOTCH, are activated upon MYT1L depletion and their chemical inhibition can rescue delayed neurogenesis in vitro. MYT1L deficiency also causes upregulation of the main cardiac sodium channel, SCN5A, and neuronal hyperactivity, which could be restored by shRNA-mediated knockdown of SCN5A or MYT1L overexpression in postmitotic neurons. Acute application of the sodium channel blocker, lamotrigine, also rescued electrophysiologic defects in vitro and behaviour phenotypes in vivo. Hence, MYT1L mutation causes both developmental and postmitotic neurological defects. However, acute intervention can normalise resulting electrophysiological and behavioural phenotypes in adulthood.
2023-02-20 | PXD037867 | Pride
Project description:MYT1L is a neuron-specific transcription factor routinely used in fibroblast-to-neuron transdifferentiation. Furthermore, mutations that reduce MYT1L function are associated with autism. Likewise, MYT1L has been hypothesized to play a role in the trajectory of neuronal specification and subtype specific maturation, but this hypothesis has not been directly tested, nor is it clear which neuron types are most impacted by MYT1L loss, and the cumulative impact of haploinsufficiency on chromatin has been unclear. In this study, we profiled 277,698 nuclei from the forebrains of wild-type and MYT1L-deficient mice at two developmental stages: E14 at the peak of neurogenesis and P21, when neurogenesis is complete. We found that MYT1L deficiency had the strongest impact on deep layer excitatory neurons, specifically disrupting their trajectory of development and preventing arrival at a mature state. We also demonstrated that MYT1L acts primarily, but not exclusively, as a transcriptional repressor in these cell types, and most effects on gene expression are cell-autonomous. Furthermore, we developed and applied single-nucleus combinatorial indexing Calling Cards (sci-CC), an exponentially scalable method to simultaneously record gene expression and longitudinal enhancer activity in single nuclei over time. We find that the disruptions persist throughout neurodevelopment as excitatory neurons were disproportionately affected. These findings illuminate the intricate role of MYT1L in orchestrating gene expression dynamics during neuronal development, providing insights into the molecular underpinnings of MYT1L syndrome.
2024-04-11 | GSE262364 | GEO
Project description:MYT1L is a neuron-specific transcription factor routinely used in fibroblast-to-neuron transdifferentiation. Furthermore, mutations that reduce MYT1L function are associated with autism. Likewise, MYT1L has been hypothesized to play a role in the trajectory of neuronal specification and subtype specific maturation, but this hypothesis has not been directly tested, nor is it clear which neuron types are most impacted by MYT1L loss, and the cumulative impact of haploinsufficiency on chromatin has been unclear. In this study, we profiled 277,698 nuclei from the forebrains of wild-type and MYT1L-deficient mice at two developmental stages: E14 at the peak of neurogenesis and P21, when neurogenesis is complete. We found that MYT1L deficiency had the strongest impact on deep layer excitatory neurons, specifically disrupting their trajectory of development and preventing arrival at a mature state. We also demonstrated that MYT1L acts primarily, but not exclusively, as a transcriptional repressor in these cell types, and most effects on gene expression are cell-autonomous. Furthermore, we developed and applied single-nucleus combinatorial indexing Calling Cards (sci-CC), an exponentially scalable method to simultaneously record gene expression and longitudinal enhancer activity in single nuclei over time. We find that the disruptions persist throughout neurodevelopment as excitatory neurons were disproportionately affected. These findings illuminate the intricate role of MYT1L in orchestrating gene expression dynamics during neuronal development, providing insights into the molecular underpinnings of MYT1L syndrome.
2024-04-11 | GSE262366 | GEO
Project description:We examined the effect of heterozygous MYT1L deficiency in human induced neurons. Increased expression of genes with MYT1L binding motifs and activation of non-neuronal genes were observed in human neurons along with deregulation of autism-associated risk genes upon depletion of MYT1L.
2023-02-14 | GSE171324 | GEO
Project description:Regulation of spatiotemporal gene expression in higher eukaryotic cells is critical for the precise and orderly development of undifferentiated progenitors into committed cell types of the adult. Recently, dynamic epigenomic regulation, including chromatin remodeling and histone modifications by transcriptional coregulator complexes, has been shown to be involved in transcriptional regulation. Precisely how these coregulator complexes exert their cell-type and developing stage-specific activity is largely unknown. In this study, we aimed to isolate the histone demethylase LSD1 complex from neural cells by biochemical purification. In so doing, we identified MyT1 as a novel LSD1 complex component. MyT1 is a neural cell-specific zinc finger factor and it forms a stable multiprotein complex with LSD1 through direct interaction. Target gene analysis using microarray and ChIP assays revealed several genes, including PTEN, that were directly regulated by the LSD1-MyT1 complex. Knockdown of either LSD1 or MyT1 derepressed the expression of endogenous target genes and inhibited cell proliferation of a neuroblastoma cell line, Neuro2a. We propose that formation of tissue-specific combinations of coregulator complexes is a critical mechanism for tissue-specific transcriptional regulation.
2014-05-20 | GSE49685 | GEO