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Hierarchical mechanisms for transcription factor-mediated reprogramming of fibroblasts to neurons

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE43916 | GEO | 2013/10/24

SECONDARY ACCESSION(S): PRJNA188177

REPOSITORIES: GEO

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Hierarchical mechanisms for transcription factor-mediated reprogramming of fibroblasts to neurons

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

Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons.

Project description:Direct lineage reprogramming is a promising approach for human disease modeling and regenerative medicine, with poorly understood mechanisms. 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. Ascl1 acts as an "on-target" pioneer factor by immediately occupying most cognate genomic sites in fibroblasts. In contrast, Brn2 and Myt1l do not access fibroblast chromatin productively on their own; instead, Ascl1 recruits Brn2 to Ascl1 sites genome wide. A unique trivalent chromatin signature in the host cells predicts the permissiveness for Ascl1 pioneering activity among different cell types. Finally, we identified Zfp238 as a key Ascl1 target gene that can partially substitute for Ascl1 during iN cell reprogramming. Thus, a precise match between pioneer factors and the chromatin context at key target genes is determinative for transdifferentiation to neurons and likely other cell types.

| S-EPMC3871197 | biostudies-literature

MicroRNAs and Ascl1 facilitate direct conversion of porcine fibroblasts into induced neurons

Project description:Direct neuronal conversion describes the process of generating induced neurons from somatic cells such as fibroblasts by overexpressing cell type-specific transcription factors. This was first achieved by expressing Brn2, Ascl1 and MytL1 in mouse fibroblasts, and was later achieved in human cells by inclusion of additional factors such as NeuroD1. Here, we present the first protocol for directly converting porcine fibroblasts into induced neurons. We used lentivirus-mediated delivery of previously identified neuronal-specifying transcription factors and microRNAs and evaluated morphology and neuronal marker expression after ten days of conversion. We found that Ascl1 and microRNAs, miR-9/9* and miR-124 together generated more neuronal cells than other conditions tested. The porcine induced neurons expressed common mature markers such as MAP2 and Synaptophysin after four weeks of conversion. Transcriptomic analysis revealed that fibroblast-specific signatures were silenced early in the conversion process, while the neuronal programs increased and matured during conversion. We generated a heterogenous population of glutamatergic and GABAergic neurons.

2020-09-22 | GSE146494 | GEO

The circadian regulator PER1 promotes cell reprogramming by inhibiting inflammatory signaling from macrophages

Project description:Fibroblasts can be reprogrammed to induced neurons (iNs) via transducion of Ascl1, Brn2, and Myt1l. To understand the roles of the circadian regulators Per1 and Per2 on the reprogramming, embryonic fibroblasts from wild type (WT), Per1-/-, and Per2-/- mice were transduced with the three genes and cells were harvested for scRNA-seq on days 4, 7, and 10 after transduction.

2023-11-09 | GSE227621 | GEO

The circadian regulator PER1 promotes cell reprogramming by inhibiting inflammatory signaling from macrophages

Project description:Fibroblasts can be reprogrammed to induced neurons (iNs) via transducion of Brn2, Ascl1, and Myt1l (BAM). To understand the roles of the circadain regulators Per1 and Per2 on the reprogramming, embryonic fibroblasts from wild type (WT), Per1-/-, and Per2-/- mice were transduced with the three genes and the cells were harvested on day 0, 2, and 4 after transduction for RNA-seq.

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Direct lineage conversion of terminally differentiated hepatocytes to functional neurons

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

Dissecting the direct reprogramming path of fibroblasts into neurons by single cell RNA-sequencing

Project description:Direct lineage reprogramming represents a remarkable conversion of cellular and transcriptome states. However, the intermediates through which individual cells progress are largely undefined. Here we used single cell RNA-seq at multiple time points to dissect direct reprogramming from mouse embryonic fibroblasts (MEFs) to induced neuronal (iN) cells. By deconstructing heterogeneity at each time point and ordering cells by transcriptome similarity rather than time we reconstructed a continuous reprogramming path. We find that overexpression of a single factor (Ascl1) results in a well-defined initialization causing cells to exit the cell cycle and re-focus gene expression through distinct neural transcription factors. However, overexpression of Ascl1 alone leads to abundant alternative fates that are suppressed by the combination of additional factors (Myt1l, Pou3f2). We find transgene silencing and emergence of alternative fates are the major efficiency limits of direct reprogramming. These data provide a high-resolution approach for understanding transcriptome states during lineage differentiation.

2016-06-08 | GSE67310 | GEO

Hierarchical mechanisms for transcription factor-mediated reprogramming of fibroblasts to neurons

Project description:Hierarchical mechanisms for transcription factor-mediated reprogramming of fibroblasts to neurons

| PRJNA188177 | ENA

Direct lineage conversion of terminally differentiated hepatocytes to functional neurons

2011-08-31 | GSE30102 | GEO

Small molecules increase direct neural conversion of human fibroblasts

Project description:Time course micro array experiment to identify transcriptional changes in response to exposure of hFLs to different combinations of small molecules during direct neuronal reprogramming hFL1 cells were transduced with conversion factors Ascl1, Brn2a and Myt1L and five days after transduction, transgene expression was activated by doxycycline. On day 3 of transgene expression, MEF medium was replaced by N2B27 medium plus small molecules, depending on the condition. Ascl1 expression was linked to GFP so that all GFP pos cells were FACS isolated at different times of exposure to small molecules (or N2B27 medium in transgene only groups). Post FACS, cells were lysed and total RNA was extracted and used as input for micro array experiments.

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