Transcription factor fluctuations underlie cell-to-cell variability in the Hedgehog response
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ABSTRACT:
PROVIDER: PRJNA838628 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19233702.fastq.gz | Fastqsanger.gz | |||
| SRR19233703_1.fastq.gz | Fastqsanger.gz | |||
| SRR19233703_2.fastq.gz | Fastqsanger.gz | |||
| SRR19233704.fastq.gz | Fastqsanger.gz | |||
| SRR19233705_1.fastq.gz | Fastqsanger.gz |
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Project description:Stochastic differences among clonal cells can initiate cell fate decisions in development or cause cell-to-cell differences in the responses to drugs or extracellular ligands. We hypothesize that some of this phenotypic variability is caused by stochastic fluctuations in the activities of transcription factors. We tested this hypothesis in NIH3T3-CG cells using the response to Hedgehog signaling as a model cellular response. Here we present evidence for the existence of distinct fast and slow responding substates of NIH3T3-CG cells. These two substates have distinct expression profiles, and fluctuations in the activity of the Prrx1 transcription factor (TF) underlie some of the differences in expression and responsiveness between fast and slow cells. We speculate that similar variability in other TFs may underlie other phenotypic differences among genetically identical cells.
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Project description:Stochastic differences among clonal cells can initiate cell fate decisions in development or cause cell-to-cell differences in the responses to drugs or extracellular ligands. We hypothesize that some of this phenotypic variability is caused by stochastic fluctuations in the activities of transcription factors. We tested this hypothesis in NIH3T3-CG cells using the response to Hedgehog signaling as a model cellular response. Here we present evidence for the existence of distinct fast and slow responding substates of NIH3T3-CG cells. These two substates have distinct expression profiles, and fluctuations in the activity of the Prrx1 transcription factor (TF) underlie some of the differences in expression and responsiveness between fast and slow cells. We speculate that similar variability in other TFs may underlie other phenotypic differences among genetically identical cells.
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Project description:Transcription factor fluctuations underlie cell-to-cell variability in the Hedgehog response [bulk-RNAseq]
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Project description:SOX2 and OCT4 are pioneer transcription factors playing a key role in embryonic stem (ES) cell self-renewal and differentiation. How temporal fluctuations in their expression levels bias lineage commitment is unknown. Here we generated knock-in reporter fusion ES cell lines allowing to monitor endogenous SOX2 and OCT4 protein fluctuations in living cells and to determine their impact on mesendodermal and neuroectodermal commitment. We found that small differences in SOX2 and OCT4 levels impact cell fate commitment in G1 but not in S phase. Elevated SOX2 levels modestly increased neuroectodermal commitment and decreased mesendodermal commitment upon directed differentiation. In contrast, elevated OCT4 levels strongly biased ES cells towards both neuroectodermal and mesendodermal fates. Using ATAC-seq on ES cells gated for different endogenous SOX2 and OCT4 levels, we found that high OCT4 levels increased chromatin accessibility at differentiation-associated enhancers. This suggests that small endogenous fluctuations of pioneer transcription factors can bias cell fate decisions by concentration-dependent priming of differentiation-associated enhancers.
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Project description:Sivakumar2011 - Hedgehog Signaling Pathway
This is the current model for the Hedgehog signaling pathway. The best data for mechanism of signaling has been worked out in Drosophila, so this model is based largely on Drosophila data. Hedgehog target genes vary from tissue to tissue, so the identities of individual target genes have not been listed. The main difference between the Drosophila and mammalian Hedgehog signaling pathways is the fact that there are three mammalian homologs of Cubitus interruptus, Gli1 Gli2 and Gli3. Some or all of the mammalian homologs may be proteolytically processed, but the data are controversial. There are two mammalian Ptc genes and three mammalian Hedgehog genes as well. The pathway for Sonic Hedgehog appears to be most similar to the Drosophila hedgehog pathway.
References:
Hedgehog signaling in animal development: paradigms and principles.
Sonic hedgehog in the nervous system: functions, modifications and mechanisms.
Hedgehog signal transduction: recent findings.
Hedgehog signaling: Costal-2 bridges the transduction gap.
This model is described in the article:
A systems biology approach to model neural stem cell regulation by notch, shh, wnt, and EGF signaling pathways.
Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S.
Omics: a Journal of Integrative Biology. 2011; 15(10):729-737
Abstract:
The Notch, Sonic Hedgehog (Shh), Wnt, and EGF pathways have long been known to influence cell fate specification in the developing nervous system. Here we attempted to evaluate the contemporary knowledge about neural stem cell differentiation promoted by various drug-based regulations through a systems biology approach. Our model showed the phenomenon of DAPT-mediated antagonism of Enhancer of split [E(spl)] genes and enhancement of Shh target genes by a SAG agonist that were effectively demonstrated computationally and were consistent with experimental studies. However, in the case of model simulation of Wnt and EGF pathways, the model network did not supply any concurrent results with experimental data despite the fact that drugs were added at the appropriate positions. This paves insight into the potential of crosstalks between pathways considered in our study. Therefore, we manually developed a map of signaling crosstalk, which included the species connected by representatives from Notch, Shh, Wnt, and EGF pathways and highlighted the regulation of a single target gene, Hes-1, based on drug-induced simulations. These simulations provided results that matched with experimental studies. Therefore, these signaling crosstalk models complement as a tool toward the discovery of novel regulatory processes involved in neural stem cell maintenance, proliferation, and differentiation during mammalian central nervous system development. To our knowledge, this is the first report of a simple crosstalk map that highlights the differential regulation of neural stem cell differentiation and underscores the flow of positive and negative regulatory signals modulated by drugs.
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Project description:Despite Hedgehog’s influence on T-cell activation and proliferation, the transcriptional targets of Gli2 in lymphocytes are not known. We therefore examined the Hedgehog-dependent transcriptional response of resting and early-stage activated T-cells in order to define their transcriptional response to Hedgehog pathway activation. We have established transgenic models where transcription of target genes by Gli2 is either constitutively activated or repressed in cells of the T-lineage. Gli2 has an N-terminal repressor domain and a C-terminal activator domain. Lck-Gli2?N2 (Gli2A) mice carry a transgene encoding a truncated form of Gli2 that acts as a permanent transcriptional activator of Hh target genes. Conversely, Lck-Gli2?C2 (Gli2R) mice express a repressor of Gli2-dependent transcription, which by binding to Gli binding sites inhibits physiological Hh-dependent transcription, and hence Hh signal transduction, in the cell. These transgenes are driven by the Lck promoter and are only expressed in T-lineage cells Purified fresh, resting CD4 cells (unstimulated) and from CD4 cells stimulated with anti-CD3/CD28 for 6h (stimulated) were analysed in order to obtain transcriptional profiles before and during the early stages of T-cell activation.
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