Small molecules modulate chromatin accessibility to promote NEUROG2-mediated fibroblast-to-neuron reprogramming
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ABSTRACT:
PROVIDER: PRJNA305691 | ENA |
REPOSITORIES: ENA
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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.
2016-11-09 | GSE75906 | 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.
2016-11-09 | GSE80639 | GEO
Project description:Pro-neural transcription factors and small molecules can induce the reprogramming of fibroblasts into functional neurons; however, the immediate-early molecular events that catalyze this conversion have not been well defined. We previously demonstrated that neurogenin 2 (NEUROG2), forskolin (F), and dorsomorphin (D) can reprogram fibroblasts into 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 chromatin accessibility and H3K27 acetylation, and synergistic transcription activated by these factors is essential to successful reprogramming. CREB1 promotes neuron survival and acts with NEUROG2 to upregulate SOX4, which co-activates NEUROD1 and NEUROD4. In addition, SOX4 targets SWI/SNF subunits and SOX4 knockdown results in extensive loss of open chromatin and abolishes reprogramming. Applying these insights, adult human glioblastoma cell and skin fibroblast reprogramming can be improved using SOX4 or chromatin-modifying chemicals.
| S-EPMC5106529 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-11-09 | GSE75912 | GEO
Project description:Small molecules modulate chromatin accessibility to promote NEUROG2-mediated fibroblast-to-neuron reprogramming [ChIP-Seq]
| PRJNA305700 | ENA
Project description:Small molecules modulate chromatin accessibility to promote NEUROG2-mediated fibroblast-to-neuron reprogramming [ATAC-seq]
| PRJNA319558 | ENA
Project description:Small molecules modulate chromatin accessibility to promote NEUROG2-mediated fibroblast-to-neuron reprogramming [RNA-seq]
| PRJNA305689 | ENA
Project description:Timeline RNAseq of fibroblast to neuron direction conversion
| PRJEB32551 | ENA
Project description:Astrocyte-to-neuron conversion has developed into a promising avenue for neuronal replacement therapy. Neurons depend critically on mitochondria function and often die by ferroptosis during the conversion process. Here we examined the extent of adequate mitochondrial reprogramming by morphology and proteome analysis. While mitochondria profoundly changed their morphology during Neurogenin2 (Neurog2) – or Achaete-scute homolog 1 (Ascl1)-mediated astrocyte-to-neuron reprogramming, we found neuron-specific mitochondrial proteins, here identified in a comprehensive proteome analysis of isolated mitochondria from primary neurons and astrocytes, to be only partially and at late stages regulated during the process. To improve this, we used dCas9 technology to induce neuron-specific mitochondrial proteins early during reprogramming. This resulted not only in increased conversion efficiency, but also in faster neuronal generation. Taken together, reprogramming mitochondria in a cell type-specific manner has powerful effects on astrocyte-to-neuron conversion, suggesting mitochondria to be a driving force in this process.
2021-03-29 | PXD014886 | Pride