Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA314536 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3210270.fastq.gz | Fastqsanger.gz | |||
| SRR3210280.fastq.gz | Fastqsanger.gz | |||
| SRR3210290.fastq.gz | Fastqsanger.gz | |||
| SRR3210300.fastq.gz | Fastqsanger.gz | |||
| SRR3210271.fastq.gz | Fastqsanger.gz |
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Project description:Cellular reprogramming using chemically defined conditions, without genetic manipulation, is a promising approach for generating clinically relevant cell types for regenerative medicine and drug discovery. However, small molecule-driven approaches for inducing lineage-specific stem cells from somatic cells across lineage boundaries have been challenging to develop. Here, we report highly efficient reprogramming of mouse fibroblasts into induced neural stem cell-like cells (ciNSLCs) using a cocktail of nine small molecules (M9). The resulting ciNSLCs closely resemble primary neural stem cells molecularly and functionally. Transcriptome analysis revealed that M9 induces a gradual and specific conversion of fibroblasts towards a neural fate. During reprogramming specific transcription factors such as Elk1 and Gli2 that are downstream of M9-induced signaling pathways bind and activate endogenous master neural genes to specify neural identity. Our study therefore provides an effective chemical approach for generating neural stem cells from mouse fibroblasts, and reveals mechanistic insights into underlying reprogramming process. Genome-wide binding of Elk1 and Gli2 was analyzed by CHIP-seq for tdMEFs from day 0 (ciNSLC), day 4 (D4), day 8 (D8) of M9-induced neural reprogramming, and ciNSLCs and pri-NPC.
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Project description:Cellular reprogramming using chemically defined conditions, without genetic manipulation, is a promising approach for generating clinically relevant cell types for regenerative medicine and drug discovery. However, small molecule-driven approaches for inducing lineage-specific stem cells from somatic cells across lineage boundaries have been challenging to develop. Here, we report highly efficient reprogramming of mouse fibroblasts into induced neural stem cell-like cells (ciNSLCs) using a cocktail of nine small molecules (M9). The resulting ciNSLCs closely resemble primary neural stem cells molecularly and functionally. Transcriptome analysis revealed that M9 induces a gradual and specific conversion of fibroblasts towards a neural fate. During reprogramming specific transcription factors such as Elk1 and Gli2 that are downstream of M9-induced signaling pathways bind and activate endogenous master neural genes to specify neural identity. Our study therefore provides an effective chemical approach for generating neural stem cells from mouse fibroblasts, and reveals mechanistic insights into underlying reprogramming process. Genome-wide epigenetic changes of H3K4me1, H3K4me3, H3K27me3, and H3K27ac were analyzed by CHIP-seq for tdMEFs from day 0 (ciNSLC), day 4 (D4), day 8 (D8) of M9-induced neural reprogramming, and ciNSLCs and pri-NPC.
2016-05-15 | E-GEOD-78977 | biostudies-arrayexpress
Project description:Cellular reprogramming using chemically defined conditions, without genetic manipulation, is a promising approach for generating clinically relevant cell types for regenerative medicine and drug discovery. However, small molecule-driven approaches for inducing lineage-specific stem cells from somatic cells across lineage boundaries have been challenging to develop. Here, we report highly efficient reprogramming of mouse fibroblasts into induced neural stem cell-like cells (ciNSLCs) using a cocktail of nine small molecules (M9). The resulting ciNSLCs closely resemble primary neural stem cells molecularly and functionally. Transcriptome analysis revealed that M9 induces a gradual and specific conversion of fibroblasts towards a neural fate. During reprogramming specific transcription factors such as Elk1 and Gli2 that are downstream of M9-induced signaling pathways bind and activate endogenous master neural genes to specify neural identity. Our study therefore provides an effective chemical approach for generating neural stem cells from mouse fibroblasts, and reveals mechanistic insights into underlying reprogramming process.
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Project description:Genome-wide chromatin landscape of chemical-induced neural stem cell reprogramming from defined fibroblasts
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Project description:Neural stem cells (NSCs) are valuable for both basic research and clinical application. We previously reported a chemical cocktail that could reprogram somatic cells into neural progenitor cells. However, the process of chemical induction is complex and the underlying mechanism remains largely elusive. Here, we identified a new culture condition that greatly promotes the efficiency of NSC generation directly from mouse fibroblasts based on our reported chemical cocktail. Transcriptome and epigenome analyses during the reprogramming process demonstrated that growth factors including IL6, FGF5 and LIF were dynamically activated and contributed to the chemical cocktail induced cell fate changes. Interestingly, fibroblast-to-NSC conversion requires the synergistic action of these growth factors. Moreover, the reprogramming capacity of both chemical cocktail and growth factors require nucleoporin Nup210 to activate endogenous neural transcription factors SoxB1 family to initiate NSC fate. Our study not only provides a novel protocol to generate NSC directly from mouse fibroblasts, but also reveals an important role of growth factors in chemical-induced cellular reprogramming.
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Project description:The chromodomain helicase DNA binding protein CHD8 is among the most frequently found de-novo mutations in autism. Unlike other autism-risk genes, CHD8 mutations appear to be fully penetrant. Despite this prominent disease involvement, relatively little is known about its molecular function. Based on sequence homology, CHD8 is believed to be a chromatin regulator but mechanisms for its genomic targeting and its function on chromatin are unclear. Here, we developed a human cell model carrying conditional CHD8 loss-of-function alleles. Remarkably, while undifferentiated human embryonic stem (ES) cells required CHD8 for survival, postmitotic neurons survived following CHD8 depletion. Chromatin accessibility revealed that CHD8 is a highly potent and general chromatin activator, enhancing transcription of its direct target genes. We also found that CHD8 genomic binding in human neurons was significantly enriched at ELK1 DNA binding motifs as previously found in other cell types. Given its prominent role as effector molecule of the MAPK/ERK pathway, we decided to further explore its relationship with CHD8. ELK1 motif-containing CHD8 binding sites showed a higher degree of chromatin opening function of CHD8 than other CHD8 binding sites. Moreover, ELK1 was required for CHD8 binding to Elk1-containing sites, but not other sites. Finally, the anti-apoptotic function of CHD8 in human ES cells could be rescued by depletion of ELK1 and the enhancement of neurogenesis by ELK1 was dependent on presence of CHD8. In summary, our results establish a clear role of CHD8 for chromatin opening and transcriptional activation and a molecular and functional interdependence of CHD8 and ELK1. These data imply the involvement of the MAPK/ERK pathway effector ELK1 in the pathogenesis of autism caused by CHD8 mutations.
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Project description:Pluripotent stem cells can be generated by pure small molecule compounds. However, only fibroblasts, a heterogeneous cell population, were reported for use in chemical reprogramming, and the efficiency is relatively low, raising the possibility that chemically induced pluripotent stem cells (CiPSCs) are derived from a specific cell subpopulation residing in fibroblast culture. Thus, it is of interest to know whether chemical reprogramming can be induced in other cell types, even using the same chemical cocktail. Here, using lineage tracing, we verify the generation of CiPSCs from fibroblasts. We further demonstrate that neural stem cells (NSCs) and small intestinal epithelial cells (IECs), cell types from the ectoderm and endoderm, respectively, can be chemically reprogrammed into pluripotent stem cells. CiPSCs derived from NSCs and IECs resemble mouse embryonic stem cells (ESCs) in terms of proliferation rate, global gene expression profiling, epigenetic status, self-renewal and differentiation capacity, and germline transmission competency. Interestingly, in the chemical reprogramming process from different cell types, a pluripotency gene Sall4 was commonly expressed in the initial stage, and the same core small molecules were required, suggesting conservatism underlying chemical reprogramming from different cell types. Moreover, the use of these small molecules should be fine-tuned to meet the requirement of reprogramming from different cell types. Together, these findings demonstrate that our reported chemical reprogramming approach can be reproduced in different cell types and suggest that chemical reprogramming is a promising strategy with the potential to be extended to more initial cell types. We analyzed the gene expression profiles of NSC-derived CiPSCs and IEC-derived CiPSCs ,using RNA-Sequencing. NSCs, IECs, and embryonic stem cells (R1) are controls.
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Project description:Gene expression profile of chemical-induced neural stem cells from defined fibroblasts
| PRJNA314469 | ENA