Direct neuronal reprogramming by temporal identity factors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA716964 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Temporal identity factors are sufficient to reprogram developmental competence of neural progenitors and shift cell fate output, but whether they can also reprogram the identity of terminally differentiated cells is unknown. To address this question, we designed a conditional gene expression system that allows rapid screening of potential reprogramming factors in mouse retinal glial cells combined with genetic lineage tracing. Using this assay, we found that co-expression of the early temporal identity transcription factors Ikzf1 and Ikzf4 is sufficient to directly convert Müller glial cells into cells that translocate to the outer nuclear layer (ONL), where photoreceptor cells normally reside. We name these “induced ONL (iONL)” cells. Using genetic lineage tracing, histological, immunohistochemical, and single-cell transcriptome and multiome analyses, we show that expression of Ikzf1/4 in Müller glia in vivo, without retinal injury, mostly generate iONL cells that share molecular characteristics with bipolar cells, although a fraction of them stain for Rxrg, a cone photoreceptor marker. Furthermore, we show that co-expression of Ikzf1 and Ikzf4 can reprogram mouse embryonic fibroblasts to induced neurons (iN) in culture by rapidly remodeling chromatin and activating a neuronal gene expression program. This work uncovers general neuronal reprogramming properties for temporal identity factors in terminally differentiated cells.
2023-05-04 | GSE169519 | GEO
Project description:Diverse reprogramming codes for neuronal identity
| PRJNA445859 | ENA
Project description:The transcriptional programs that establish neuronal identity evolved to produce a rich diversity of neuronal cell types that arise sequentially during development. Remarkably, transient expression of certain transcription factors (TFs) can also endow non-neural cells with neuronal properties. To decipher the relationship between reprogramming factors and transcriptional networks that produce neuronal identity and diversity, we screened ~600 TF pairs and identified 76 that produce induced neurons (iNs) from fibroblasts. By intersecting the transcriptomes of iNs with those of endogenous neurons, we define a “core” cell-autonomous neuronal signature. The iNs also exhibit diversity; each TF pair produces iNs with unique transcriptional patterns that can predict their pharmacological responses. By linking distinct TF input “codes” to defined transcriptional outputs, this study uncovers cell autonomous features of neuronal identity and expands the reprogramming toolbox to enable more facile engineering of induced neurons with desired patterns of gene expression and related functional properties.
2018-05-10 | GSE112381 | GEO
Project description:Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming
| PRJNA1063270 | ENA
Project description:Direct lineage reprogramming involves the conversion of cellular identity. Single-cell technologies are useful for deconstructing the considerable heterogeneity that emerges during lineage conversion. However, lineage relationships are typically lost during cell processing, complicating trajectory reconstruction. Here we present ‘CellTagging’, a combinatorial cell-indexing methodology that enables parallel capture of clonal history and cell identity, in which sequential rounds of cell labelling enable the construction of multi-level lineage trees. CellTagging and longitudinal tracking of fibroblast to induced endoderm progenitor reprogramming reveals two distinct trajectories: one leading to successfully reprogrammed cells, and one leading to a ‘dead-end’ state, paths determined in the earliest stages of lineage conversion. We find that expression of a putative methyltransferase, Mettl7a1, is associated with the successful reprogramming trajectory; adding Mettl7a1 to the reprogramming cocktail increases the yield of induced endoderm progenitors. Together, these results demonstrate the utility of our lineage-tracing method for revealing the dynamics of direct reprogramming.
2018-09-25 | GSE99915 | GEO
Project description:Despite the widespread interest in direct neuronal reprogramming, the mechanisms underpinning fate conversion remain largely unknown. Our study revealed a critical time point after which cells either successfully convert into neurons or succumb to cell death. Co-transduction with Bcl-2 greatly improved negotiation of this critical point by faster neuronal differentiation. Surprisingly, mutants with reduced or no affinity for Bax demonstrated that Bcl-2 exerts this effect by an apoptosis-independent mechanism. Consistent with a caspase-independent role, ferroptosis inhibitors potently increased neuronal reprogramming by inhibiting lipid peroxidation occurring during fate conversion. Genome-wide expression analysis confirmed that treatments promoting neuronal reprogramming elicit an anti-oxidative stress response. Importantly, coexpression of Bcl-2 and anti-oxidative treatments lead to an unprecedented improvement in glial-to-neuron conversion after traumatic brain injury in vivo, underscoring the relevance of these pathways in cellular reprograming irrespective of cell type, in vitro and in vivo. We performed gene expression microarray analysis on mouse embryonic fibroblasts transfected with a viral vector for Ascl1 or empty vector. Cells were then cultured in the absence or presence of forskolin
2016-06-29 | E-GEOD-70921 | biostudies-arrayexpress
Project description:Despite the widespread interest in direct neuronal reprogramming, the mechanisms underpinning fate conversion remain largely unknown. Our study revealed a critical time point after which cells either successfully convert into neurons or succumb to cell death. Co-transduction with Bcl-2 greatly improved negotiation of this critical point by faster neuronal differentiation. Surprisingly, mutants with reduced or no affinity for Bax demonstrated that Bcl-2 exerts this effect by an apoptosis-independent mechanism. Consistent with a caspase-independent role, ferroptosis inhibitors potently increased neuronal reprogramming by inhibiting lipid peroxidation occurring during fate conversion. Genome-wide expression analysis confirmed that treatments promoting neuronal reprogramming elicit an anti-oxidative stress response. Importantly, coexpression of Bcl-2 and anti-oxidative treatments lead to an unprecedented improvement in glial-to-neuron conversion after traumatic brain injury in vivo, underscoring the relevance of these pathways in cellular reprograming irrespective of cell type, in vitro and in vivo. We performed gene expression microarray analysis on mouse embryonic fibroblasts transfected with a viral vector for Ascl1 or empty vector. Cells were then cultured in the absence or presence of forskolin
2015-12-11 | E-GEOD-60790 | biostudies-arrayexpress
Project description:Late-onset Alzheimer’s disease (LOAD) is the most common form of AD. However, modeling sporadic LOAD, without clear genetic predispositions, to capture hallmark neuronal pathologies such as extracellular amyloid-β (Aβ) plaque deposition, intracellular tau tangles, and neuronal loss, remains an unmet need. Here, we demonstrate that neurons generated by microRNA-based direct reprogramming of fibroblasts from patients affected by autosomal dominant AD (ADAD) and LOAD in a three-dimensional (3D) environment, effectively recapitulate key neuropathological features of AD without additional cellular or genetic insults. These LOAD neurons exhibit Aβ-dependent neurodegeneration, as treatment with β- or γ-secretase inhibitors before (but not subsequent to) Aβ deposit formation mitigated neuronal death. Moreover, inhibiting age-associated retrotransposable elements (RTEs) in LOAD neurons reduced both Ab deposition and neurodegeneration. Our study underscores the efficacy of modeling late-onset neuropathology of LOAD through high-efficiency microRNA-based neuronal reprogramming.
2024-08-05 | GSE252932 | GEO
Project description:Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming III
| PRJNA1111938 | ENA
Project description:Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming II
| PRJNA1064158 | ENA