Dedifferentiation-derived neural stem cells exhibit perturbed temporal progression
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ABSTRACT:
PROVIDER: PRJNA935471 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23490964.fastq.gz | Fastqsanger.gz | |||
| SRR23490965.fastq.gz | Fastqsanger.gz | |||
| SRR23490966.fastq.gz | Fastqsanger.gz | |||
| SRR23490967.fastq.gz | Fastqsanger.gz | |||
| SRR23490968_1.fastq.gz | Fastqsanger.gz |
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Project description:One of the key regulatory mechanisms of brain size and neuronal diversity is through control of NB identity via cell fate maintenance. Dedifferentiation is the reversion of differentiated cells to a stem cell like fate, whereby, the gene expression program of mature cells is altered and genes associated with multipotency are expressed. Beyond the fact that misexpression of these factors and pathways caused the formation of ectopic NBs, whether these dedifferentiated NBs faithfully produce the correct number and types of neurons or glial cells, or undergo timely terminal differentiation, has not been assessed. These characteristics are key determinants of overall CNS size and function, thus are important parameters when considering whether dedifferentiation leads to tumourigenesis or can be appropriately utilized for regenerative purposes. Appropriate terminal differentiation as well as neuronal diversity are key characteristics of NSCs, and are specified through temporal patterning of the NSCs driven by the successive expression of temporal transcription factors (tTFs). In this study, we found that ectopic NSCs induced via bHLH transcription factor Deadpan (Dpn) expression in the optic lobes of the developing Drosophila CNS fail to undergo appropriate temporal progression, where they express mid-tTF, Sloppy-paired 1 (Slp-1) at the expense of late-tTF Tailless (Tll); consequently generating an excess of Twin of eyeless (Toy) positive neurons and fewer Reversed polarity (Repo) positive glial cells. Dpn overexpression also resulted in stalled progression through the cell cycle, and a failure to undergo timely terminal differentiation. Mechanistically, DamID studies demonstrated that Dpn directly binds to both Dichaete (D), a Sox-box transcription factor known to repress Slp-1, as well as a number of cell cycle genes. Promoting cell cycle progression or overexpression of D were able to re-trigger the progression of the temporal series in dedifferentiated NBs, restoring both neuronal diversity and timely NB terminal differentiation.
2023-05-24 | GSE225409 | GEO
Project description:Dedifferentiation is the reversion of mature cells to a stem cell-like fate, whereby gene expression programs are altered and genes associated with multipotency are (re)expressed. Misexpression of multipotency factors and pathways causes the formation of ectopic NSCs. Whether dedifferentiated NSCs faithfully produce the correct number and types of progeny, or undergo timely terminal differentiation, has not been assessed. Here we show that ectopic NSCs induced via bHLH transcription factor Deadpan (Dpn) expression fail to undergo appropriate temporal progression by constantly expressing mid-temporal transcription factor, (tTF), Sloppy-paired 1 (Slp-1). Consequently, this resulted in impaired terminal differenation and generated an excess of Twin of eyeless (Toy) positive neurons at the expense of Reversed polarity (Repo) positive glial cells. Preference for a mid-temporal fate in these NBs is concordant with an enriched binding of Dpn at mid-tTF loci and a depletion of Dpn binding at early and late tTF loci. Re-triggering the temporal series via manipulatsion of the temporal series or cell cycle is sufficient to reinstate neuronal diversity and timely termination.
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Project description:Dedifferentiation is the reversion of mature cells to a stem cell-like fate, whereby gene expression programs are altered and genes associated with multipotency are (re)expressed. Misexpression of multipotency factors and pathways causes the formation of ectopic neural stem cells (NSCs). Whether dedifferentiated NSCs faithfully produce the correct number and types of progeny, or undergo timely terminal differentiation, has not been assessed. Here, we show that ectopic NSCs induced via bHLH transcription factor Deadpan (Dpn) expression fail to undergo appropriate temporal progression by constantly expressing mid-temporal transcription factor(tTF), Sloppy-paired 1/2 (Slp). Consequently, this resulted in impaired terminal differenation and generated an excess of Twin of eyeless (Toy)-positive neurons at the expense of Reversed polarity (Repo)-positive glial cells. Preference for a mid-temporal fate in these ectopic NSCs is concordant with an enriched binding of Dpn at mid-tTF loci and a depletion of Dpn binding at early- and late-tTF loci. Retriggering the temporal series via manipulation of the temporal series or cell cycle is sufficient to reinstate neuronal diversity and timely termination.
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Project description:Although transcription factor(TF)s regulate differentiation-related processes, including dedifferentiation and direct conversion, functional interactions between TFs regulating these processes are not well understood. Here we show that TFs preventing dedifferentiation are able to induce direct conversion. Using a neural lineage cell line and a large number of TFs expressed in it, we found a subset of TFs whose overexpression strongly interfered with dedifferentiation triggered by a procedure to induce induced pluripotent stem cells (iPSC), through a maintenance mechanism of the cell-type-specific transcriptional profile. Strikingly, the maintenance activity of the interfering TF set was strong enough to induce the cell line-specific transcriptional profile when overexpressed in a heterologous cell type. In addition, TFs that interfered with dedifferentiation in hepatic lineage cells involved known TFs with induction activity for hepatic lineage cells. Our results suggest that dedifferentiation suppresses a cell-type-specific transcriptional profile, which is primarily maintained by a small subset of TFs capable of inducing direct conversion. We anticipate that this functional correlation might be applicable in various cell types, which may include cancer cells, and might facilitate identification of TFs with induction activity to understand differentiation and tumorigenesis Examination of binding of 3 transcription factors and histone modifications in Neural progenitor like cells.
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Project description:Pediatric neural tumors are initiated during embryonic/fetal stages and rapidly become malignant despite carrying few genetic alterations. However, the molecular basis of this early malignant susceptibility remains unknown. During Drosophila development, malignant neural tumors can arise from single gene inactivation triggering dedifferentiation towards a neural stem cell (NSC)-like state. Here, we find that these tumors originate from a sub-population of early-born neural progeny that transiently co-express the mRNA-binding proteins Lin-28 and Imp/IGF2BP, and the transcription factor Chinmo. These three genes compose an early growth module that is co-opted in a subset of dedifferentiated cells to propagate unlimited proliferation. In late NSCs, Chinmo, Imp and Lin-28 are silenced by temporal transcription factors for timely termination of neurogenesis. Consequently, late-born progeny do not express the module and become refractory to malignant transformation. Thus, this study identifies the NSC-intrinsic developmental program that predisposes neural progeny to malignant transformation according to their birth order.
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Project description:Melanoma dedifferentiation has been reported as a state of cellular resistance to targeted therapies and immunotherapies as cancer cells revert to a more primitive cellular phenotype. Here we show that, counterintuitively, the biopsies of patient tumors that respond to anti-programmed cell death receptor 1 (PD-1) therapy decreased expression of melanocytic markers and increased neural crest markers, suggesting treatment-induced dedifferentiation. When modeling the effects in vitro, we documented that melanoma cell lines that were originally melanocytic differentiated underwent a process of neural crest dedifferentiation when continuously exposed to interferon gamma (IFNγ), through a global chromatin landscape changes leading to enrichment in specific hyperaccessible chromatin regions. The IFNγ-induced dedifferentiation signature corresponded with improved outcomes in patients with melanoma, challenging the notion that neural crest dedifferentiation is entirely an adverse phenotype.
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Project description:Melanoma dedifferentiation has been reported as a state of cellular resistance to targeted therapies and immunotherapies as cancer cells revert to a more primitive cellular phenotype. Here we show that, counterintuitively, the biopsies of patient tumors that respond to anti-programmed cell death receptor 1 (PD-1) therapy decreased expression of melanocytic markers and increased neural crest markers, suggesting treatment-induced dedifferentiation. When modeling the effects in vitro, we documented that melanoma cell lines that were originally melanocytic differentiated underwent a process of neural crest dedifferentiation when continuously exposed to interferon gamma (IFNγ), through a global chromatin landscape changes leading to enrichment in specific hyperaccessible chromatin regions. The IFNγ-induced dedifferentiation signature corresponded with improved outcomes in patients with melanoma, challenging the notion that neural crest dedifferentiation is entirely an adverse phenotype.
2021-05-10 | GSE152755 | GEO
Project description:Neural stem cells (NSCs) generate highly diverse neurons over time by acquiring new features, a phenomenon called as temporal patterning. However the mechanisms underlying temporal patterning still remains poorly understood. Here, we describe a method that allows to isolate different temporal stages of Drosophila transit amplifying cells called intermediate neural porgenitors (INPs). We identified odd-paired (opa) as the regulator of the transition from first to second temporal stages, which are defined by D and Grh expression. We demonstrated that opa is required for correct neural output and brain morphology. We showed that opa achieves this transition via repressing D. Together with upstream SWI/SNF complex, D and opa forms an incoheren feed forward loop, which results in successive expression of temporal identities.
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Project description:We report RNA Seq analysis using Illumina nextSeq500 of human beta cells EndoC-BH1 treated with FGF2 to induce dedifferentiation. FGF2 treatment induced dedifferentiation of EndoC-BH1 cells. Indeed, we observed a strong decrease in expression of β-cell markers, (INS, MAFB, SLC2A2, SLC30A8 and GCK). Opposingly, we identifed positive markers of human β cell dedifferentiation, as attested by increased expression of mature β-cell disallowed transcription factors (MYC, HES1, SOX9 and NEUROG3). Interestingly, our temporal analysis revealed that loss of expression of β cell specific markers preceded the induction of β cell disallowed genes.
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Project description:Temporal patterning of neural progenitors is an evolutionarily conserved strategy for generating neuronal diversity. Type II neural stem cells in the Drosophilacentral brain produce transit-amplifying intermediate neural progenitors (INPs) that exhibit temporal patterning. However, the known temporal factors cannotaccount for the neuronal diversity in the adult brain. To search for new temporal factors, we developed NanoDam, which enablesrapid genome-wide profiling of endogenously-tagged proteins in vivowith a singlegenetic cross.Mapping the targets of known temporal transcription factorswith NanoDamidentified Homeobrain and Scarecrow (ARX and NKX2.1 orthologues) as novel temporal factors. We show that Homeobrainand Scarecrow define middle-aged and late INP temporal windows and play a role in cellular longevity. Strikingly, Homeobrain and Scarecrow have conserved functions as temporal factors in the developing visual system.NanoDam enables rapid cell type-specific genome-wideprofiling with temporal resolution and can be easily adapted for use in higher organisms.
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