Reprogramming effect of Neurog2-9SA on adult mouse Muller glial cells [mutliomics]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE309445 | GEO | 2025/10/02
REPOSITORIES: GEO
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Project description:Pro-neural transcription factors and small molecules can induce the transdifferentiation of fibroblasts into functional neurons; however, a molecular mechanism detailing the immediate-early events that catalyze this conversion has not been well defined. We previously demonstrated that NEUROG2, forskolin (F), and dorsomorphin (D) can induce functional neurons with high-efficiency. Here, we used this model to define the genetic and epigenetic events that initiate an acquisition of neuronal identity. We demonstrate that NEUROG2 is a pioneer factor, FD enhances both genome-wide NEUROG2 chromatin occupancy and H3K27 acetylation, and synergistic transcription by these factors is essential to successful reprogramming. CREB1, activated by FD, promotes neuron survival and acts with NEUROG2 to upregulate SOX4, which co-activates NEUROD1 and NEUROD4. In addition to this hierarchical function, SOX4 targets SWI/SNF subunits and SOX4 knockdown results in extensive loss of open chromatin and abolishes reprogramming. Applying these insights, adult human glioblastoma and skin fibroblast reprogramming was improved using SOX4, SMARCA4, and chromatin modifying chemicals.
2016-11-09 | GSE75910 | GEO
Project description:Pro-neural transcription factors and small molecules can induce the transdifferentiation of fibroblasts into functional neurons; however, a molecular mechanism detailing the immediate-early events that catalyze this conversion has not been well defined. We previously demonstrated that NEUROG2, forskolin (F), and dorsomorphin (D) can induce functional neurons with high-efficiency. Here, we used this model to define the genetic and epigenetic events that initiate an acquisition of neuronal identity. We demonstrate that NEUROG2 is a pioneer factor, FD enhances both genome-wide NEUROG2 chromatin occupancy and H3K27 acetylation, and synergistic transcription by these factors is essential to successful reprogramming. CREB1, activated by FD, promotes neuron survival and acts with NEUROG2 to upregulate SOX4, which co-activates NEUROD1 and NEUROD4. In addition to this hierarchical function, SOX4 targets SWI/SNF subunits and SOX4 knockdown results in extensive loss of open chromatin and abolishes reprogramming. Applying these insights, adult human glioblastoma and skin fibroblast reprogramming was improved using SOX4, SMARCA4, and chromatin modifying chemicals.
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Project description:Pro-neural transcription factors and small molecules can induce the transdifferentiation of fibroblasts into functional neurons; however, a molecular mechanism detailing the immediate-early events that catalyze this conversion has not been well defined. We previously demonstrated that NEUROG2, forskolin (F), and dorsomorphin (D) can induce functional neurons with high-efficiency. Here, we used this model to define the genetic and epigenetic events that initiate an acquisition of neuronal identity. We demonstrate that NEUROG2 is a pioneer factor, FD enhances both genome-wide NEUROG2 chromatin occupancy and H3K27 acetylation, and synergistic transcription by these factors is essential to successful reprogramming. CREB1, activated by FD, promotes neuron survival and acts with NEUROG2 to upregulate SOX4, which co-activates NEUROD1 and NEUROD4. In addition to this hierarchical function, SOX4 targets SWI/SNF subunits and SOX4 knockdown results in extensive loss of open chromatin and abolishes reprogramming. Applying these insights, adult human glioblastoma and skin fibroblast reprogramming was improved using SOX4, SMARCA4, and chromatin modifying chemicals.
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Project description:In mammals, loss of retinal cells due to disease or trauma is an irreversible process which can lead to blindness. Interestingly, regeneration of retinal neurons is a well-established process in some non-mammalian vertebrates and is driven by the Muller glia (MG), which are able to re-enter the cell cycle and reprogram into neurogenic progenitors upon retinal injury or disease. Progress has been made to restore this mechanism in mammals to promote retinal regeneration: MG can be stimulated to generate new neurons in vivo in the adult mouse retina after the over-expression of the pro-neural transcription factor Ascl1. In this study, we applied the same strategy to reprogram human MG derived from fetal retina and retinal organoids into neurons. Combining scRNA-seq, scATAC-seq, Immunofluorescence, and electrophysiology we demonstrate that human MG can be reprogrammed into neurogenic cells in vitro.
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Project description:Cultured adult mouse dorsal root ganglia (DRG) cells exhibit glial sensory progenitor properties in vitro. Therefore, they might be a good starter cell for reprogramming into sensory neurons. Here, we infected them with the retroviral vector Neurog2-Neurog1-DsRed to induce sensory neuron development and analyzed by scRNAseq at 14 days post infection whether infected cells show properties of sensory neurons such as nociceptors. After 10x Genomics, data analysis of 4,549 individual cells indicated the generation of neurons, but at an immature cell state.
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Project description:This experiment studies retinal regeneration using a zebrafish model with a focus on Muller glia reprogramming.
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Project description:This experiment studies retinal regeneration using a zebrafish model with a focus on Muller glia reprogramming.
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Project description:Regenerative neuroscience aims to stimulate endogenous repair mechanisms in the nervous system to replace neurons that have been lost from degenerative diseases or trauma. In the retina, many non-mammalian vertebrate species spontaneously regenerate retinal neurons from glial cells, through an injury-induced reprogramming of the cells to a retinal progenitor state. Recently, we have reported that engineering mouse Muller glia to express a retinal progenitor gene, the proneural transcription factor, Ascl1, is sufficient to stimulate neurogenesis in the glia to generate functional neurons. However, this process is inefficient and only a third of the Ascl1-expressing glia generate new neurons. Here we test whether proneural transcription factors of the Atoh1/7 class can further promote the neurogenic capacity of MG. We report that the combination of Ascl1:Atoh1 is remarkably efficient at stimulating neurogenesis (>80% expressing cells), even in the absence of retinal injury or TSA. We use electrophysiology and scRNA-seq to demonstrate that Ascl1:Atoh1 generates a diversity of retinal neuron types with the majority expressing characteristics of retinal ganglion cells. Overall, our results provide a proof-of-principle that transcription factors that are normally sequentially active in cell fate specification, can when combined, substantially improve glial reprogramming to neurons and expand the repertoire of cell fates that can be regenerated in the adult mouse retina. The ability to stimulate the neurogenic potential of glia in adult mice with high efficiency is a key step towards translation of this approach to repair the central nervous system.
2021-10-19 | GSE184286 | GEO
Project description:Diseases and damage to the retina lead to losses in retinal neurons and eventual visual impairment. Although the mammalian retina has no inherent regenerative capabilities, fish have robust regeneration from Müller glia (MG). Recently, we have shown that driving expression of Ascl1 in adult mouse MG stimulates neurogenesis similar to fish regeneration. The regeneration observed in the mouse is limited in the variety of neurons that can be derived from MG; Ascl1-expressing MG primarily generate bipolar cells. To better understand the limits of MG-based regeneration in mouse retinas, we used ATAC- and RNA-seq to compare newborn progenitors with MG. Our analysis demonstrated striking similarities between MG and progenitors, with losses in regulatory motifs for neurogenesis genes. Young MG were found to have intermediate expression profiles and accessible DNA, which is mirrored in the ability of Ascl1 to direct bipolar neurogenesis in young MG. When comparing what makes bipolar and photoreceptor cells distinct from glial cells, we find that bipolar-specific accessible regions are more frequently linked to bHLH motifs and Ascl1 binding, indicating that Ascl1 preferentially binds to bipolar regions. Overall, our analysis indicates a loss of neurogenic gene expression and motif accessibility during glial maturation that may prevent efficient reprogramming.
2020-08-19 | GSE137318 | GEO
Project description:The retina is often subjected to tractional forces in a variety of conditions, for instance, pathological myopia, proliferative vitreoretinopathy. As the predominant glial element in the sensory retina, Muller cells are responsible for the homeostatic and metabolic support of retinal neurons and active players in virtually all forms of retinal injury and disease. Besides, Muller cells span the entire retinal thickness, extending from the inner to the outer limiting membranes, with cell bodies located in the inner nuclear layer and lateral processes expanding into the plexiform layers of the tissue. Because of this unique morphology, Muller cells can sense even minute changes in the retinal structure because of the mechanical stretching of their long processes or side branches. Thus, it’s reasonable to infer that Muller cells also participate in ocular diseases when the retina is overstretched. In this study, we aim to investigate the whole genome regulation of Muller cells under mechanical stretching, which may help in excluding possible molecular mechanisms that would account for many retinal diseases in which the retina is often subjected to mechanical forces. We used microarrays to identify patterns of gene expression changes induced by cyclic mechanical stretching in Muller cells.
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