Direct lineage conversion of terminally differentiated hepatocytes to functional neurons
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE30102 | GEO | 2011/08/31
SECONDARY ACCESSION(S): PRJNA143891
REPOSITORIES: GEO
Similar Datasets
Project description:Mouse fibroblasts and hepatocyte can be directly reprogrammed to induced neuronal (iN) cells. Genome-wide expression analysis showed that Hep-iN cells had not only induced a neuronal transcriptional program but also effectively silenced the hepatocyte transcriptome suggesting that the reprogramming factors lead to a binary lineage switch decision rather than an induction of hybrid phenotypes. Similarly, the fibroblast-specific transcriptional program was downregulated in fibroblast-derived iN cells. BAM = infection with the 3 factors (Ascl1 - Brn2 - Myt1l) . ATT = Hepatocytes_derived_induced_neurons derived from TauGFP-AlbCre-R26-lsl-tomato Total RNA obtained from MEFs subjected to 21 days lentivirus infection for neuronal induction compared to uninfected MEFs.
2011-08-30 | E-GEOD-30102 | biostudies-arrayexpress
Project description:Here we reveal a hierarchical mechanism in the direct conversion of fibroblasts into induced neuronal (iN) cells mediated by the transcription factors Ascl1, Brn2, and Myt1l.
2013-10-24 | GSE43916 | GEO
Project description:Here we reveal a hierarchical mechanism in the direct conversion of fibroblasts into induced neuronal (iN) cells mediated by the transcription factors Ascl1, Brn2, and Myt1l. Examination of global transcriptional changes and mapping genome-wide transcription factors occupancy at distinct time points during the transdifferentiation process
2013-04-10 | E-GEOD-43916 | biostudies-arrayexpress
Project description:Transdifferentiation of fibroblasts into induced Neuronal cells (iNs) by neuronal-specific transcription factors Brn2, Myt1l and Ascl1 is a paradigmatic example of inter-lineage conversion across epigenetically distant cells. Despite tremendous progress on the transcriptional hierarchy underlying transdifferentiation, the enablers of the concomitant epigenome resetting remain to be elucidated. Here we investigated the role of KMT2A and KMT2B, two histone H3 lysine 4 methylases with cardinal roles in development, through individual and combined inactivation. We found that Kmt2b, whose human homologue’s mutations cause dystonia, is selectively required for iN conversion through the suppression of the alternative myocyte program and the induction of neuronal maturation genes.
2018-09-29 | GSE120635 | GEO
Project description:Transdifferentiation of fibroblasts into induced Neuronal cells (iNs) by neuronal-specific transcription factors Brn2, Myt1l and Ascl1 is a paradigmatic example of inter-lineage conversion across epigenetically distant cells. Despite tremendous progress on the transcriptional hierarchy underlying transdifferentiation, the enablers of the concomitant epigenome resetting remain to be elucidated. Here we investigated the role of KMT2A and KMT2B, two histone H3 lysine 4 methylases with cardinal roles in development, through individual and combined inactivation. We found that Kmt2b, whose human homologue’s mutations cause dystonia, is selectively required for iN conversion through the suppression of the alternative myocyte program and the induction of neuronal maturation genes.
2018-09-26 | GSE120440 | GEO
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.
2023-03-02 | GSE222072 | GEO
Project description:Direct reprogramming from fibroblasts to neurons induces widespread cellular and transcriptional reconfigurations. In this study, we characterized global epigenomic changes during direct reprogramming using whole-genome base-resolution DNA methylome (mC) sequencing. We found that the pioneer transcription factor Ascl1 alone is sufficient for inducing robust non-CG methylation (mCH) accumulation in reprogrammed cells, but co-expression of Brn2 and Mytl1 was required to establish a global mCH pattern reminiscent of mature cortical neurons. Ascl1 alone induced strong promoter CG methylation (mCG) of fibroblast specific genes, while BAM overexpression additionally targets a competing myogenic program and directs a more faithful conversion to neuronal cells. Ascl1 induces local demethylation at its binding sites. Surprisingly, co-expression with Brn2 and Mytl1 inhibited the ability of Ascl1 to induce demethylation, suggesting a contextual regulation of transcription factor - epigenome interaction. Finally, we found that de novo methylation by DNMT3A is required for efficient neuronal reprogramming.
2019-01-14 | GSE111283 | 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: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: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