Single-cell transcriptome analysis of Myt1l mutant mouse cortices at birth.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE171326 | GEO | 2023/02/14
REPOSITORIES: GEO
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Project description:We examined the effect of Myt1l deficiency in the cortices of mice during developement. Homozygous Myt1l deficiency resulted in postnatal lethality, and mutant mice presented gene expression changes associated with developmental delays and resembled changes observed in autism spectrum disorder patients.
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Project description:We examined the effect of Myt1l deficiency in the neurons of mice. Homozygous Myt1l deficiency resulted in postnatal lethality, and mutant mice presented gene expression changes associated with developmental delays and resembled changes observed in autism spectrum disorder patients.
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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.
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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.
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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.
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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.
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Project description:We examined the effect of Wnt and/or Notch inhibition in the context 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.
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Project description:The goal of the study was to compare gene expression of P0 wild-type, P0 Fezf2-/- cortices, and Fezf2-/-; Fezf2-EnR cortices. Total RNAs were isolated from P0 cortices dissected from wild-type (n=3), Fezf2-/- mice (n=4), and Fezf2-/-; Fezf2-EnR cortices (n=2), following Qiagen RNAeasy kit instruction.Sequence libraries were made following Illumina RNA PolyA library preparation guide.The libaries were pair-end sequenced (150nt per end). Differentially expressed genes were identified by DESEQ.
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Project description:In vitro studies indicate the neurodevelopmental disorder gene Myelin Transcription Factor 1 Like (MYT1L) suppresses non-neuronal lineage genes during fibroblast-to-neuron direct differentiation. However, MYT1L’s molecular and cellular functions during differentiation in the mammalian brain have not been fully characterized. Here, we found that MYT1L loss leads to up-regulated deep layer (DL) but down-regulated upper layer (UL) neuron gene expression, corresponding to an increased ratio of DL/UL neurons in mouse cortex. To define potential mechanisms, we conducted Cleavage Under Targets & Release Using Nuclease (CUT&RUN) to map MYT1L binding targets in mouse developing cortex and adult prefrontal cortex (PFC), and to map epigenetic changes due to MYT1L mutation. We found MYT1L mainly binds to open chromatin, but with different transcription factor co-occupancies between promoters and enhancers. Likewise, multi-omic dataset integration revealed that, at promoters, MYT1L loss does not change chromatin accessibility but does increase H3K4me3 and H3K27ac, activating both a subset of earlier neuronal development genes as well as BCL11B, a key regulator for DL neuron development. Meanwhile, we discovered that MYT1L normally represses the activity of neurogenic enhancers associated with neuronal migration and neuronal projection development by closing chromatin structures and promoting removal of active histone marks. Further, we show MYT1L interacts with SIN3B and HDAC2 in vivo, providing potential mechanisms underlying any repressive effects on histone acetylation and gene expression. Overall, our findings provide a comprehensive map of MYT1L binding in vivo and mechanistic insights to how MYT1L facilitates neuronal maturation.
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