Multiple layers of molecular controls modulate self-renewal and neuronal lineage specification of embryonic stem cells

Yeo, G; Coufal, Nicole G.; Aigner, Stefan; Winner, Beate; Scolnick, Jonathan; Marchetto, Maria C.; Muotri, Alysson R.; Carson, Christian T.; Gage, Fred H.

doi:10.1093/hmg/ddn065

Cited by 16 publications

(9 citation statements)

References 80 publications

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“…In addition, some enhancers are also marked by RNA polymerase II and eRNA (enhancer RNA) transcripts ( 15 , 16 ). Embryonic stem (ES) cell differentiation has provided insight into the chromatin structure at the ‘ground’ state ( 17 , 18 ) as well as information on transitions during the differentiation of specific cell types such as neuronal progenitors ( 19 ). It has been shown that many developmental regulatory genes posses a ‘bivalent domain’ structure comprised of a broad H3K27me3 and a narrow H3K4me3 region at their promoters ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

Identification ofin vivoDNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during forebrain and lens development

et al. 2015

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The transcription factor Pax6 is comprised of the paired domain (PD) and homeodomain (HD). In the developing forebrain, Pax6 is expressed in ventricular zone precursor cells and in specific subpopulations of neurons; absence of Pax6 results in disrupted cell proliferation and cell fate specification. Pax6 also regulates the entire lens developmental program. To reconstruct Pax6-dependent gene regulatory networks (GRNs), ChIP-seq studies were performed using forebrain and lens chromatin from mice. A total of 3514 (forebrain) and 3723 (lens) Pax6-containing peaks were identified, with ∼70% of them found in both tissues and thereafter called ‘common’ peaks. Analysis of Pax6-bound peaks identified motifs that closely resemble Pax6-PD, Pax6-PD/HD and Pax6-HD established binding sequences. Mapping of H3K4me1, H3K4me3, H3K27ac, H3K27me3 and RNA polymerase II revealed distinct types of tissue-specific enhancers bound by Pax6. Pax6 directly regulates cortical neurogenesis through activation (e.g. Dmrta1 and Ngn2) and repression (e.g. Ascl1, Fezf2, and Gsx2) of transcription factors. In lens, Pax6 directly regulates cell cycle exit via components of FGF (Fgfr2, Prox1 and Ccnd1) and Wnt (Dkk3, Wnt7a, Lrp6, Bcl9l, and Ccnd1) signaling pathways. Collectively, these studies provide genome-wide analysis of Pax6-dependent GRNs in lens and forebrain and establish novel roles of Pax6 in organogenesis.

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Section: Introductionmentioning

confidence: 99%

Identification ofin vivoDNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during forebrain and lens development

et al. 2015

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“…Comparisons of microRNA–mediated repression in different mRNA isoforms has been successfully used to associate MRE sites with functions in many studies, such as the prediction of target mRNAs [37-41], the influence of intron retention on human mRNA [42], cellular proliferation and differentiation [12,43], and cancer [44]. The effect of fine-tuning at the splicing level would be negligible if the associated MREs are not highly repressive.…”

Section: Resultsmentioning

confidence: 99%

Fine-tuning of microRNA-mediated repression of mRNA by splicing-regulated and highly repressive microRNA recognition element

Chiou²,

Chiu³

et al. 2013

BMC Genomics

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BackgroundMicroRNAs are very small non-coding RNAs that interact with microRNA recognition elements (MREs) on their target messenger RNAs. Varying the concentration of a given microRNA may influence the expression of many target proteins. Yet, the expression of a specific target protein can be fine-tuned by alternative cleavage and polyadenylation to the corresponding mRNA.ResultsThis study showed that alternative splicing of mRNA is a fine-tuning mechanism in the cellular regulatory network. The splicing-regulated MREs are often highly repressive MREs. This phenomenon was observed not only in the hsa-miR-148a-regulated DNMT3B gene, but also in many target genes regulated by hsa-miR-124, hsa-miR-1, and hsa-miR-181a. When a gene contains multiple MREs in transcripts, such as the VEGF gene, the splicing-regulated MREs are again the highly repressive MREs. Approximately one-third of the analysable human MREs in MiRTarBase and TarBase can potentially perform the splicing-regulated fine-tuning. Interestingly, the high (+30%) repression ratios observed in most of these splicing-regulated MREs indicate associations with functions. For example, the MRE-free transcripts of many oncogenes, such as N-RAS and others may escape microRNA-mediated suppression in cancer tissues.ConclusionsThis fine-tuning mechanism revealed associations with highly repressive MRE. Since high-repression MREs are involved in many important biological phenomena, the described association implies that splicing-regulated MREs are functional. A possible application of this observed association is in distinguishing functionally relevant MREs from predicted MREs.

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“…Within these heterogeneous cell populations, neural rosettes are formed from which neural cells may be separated from other cell types. 39, 40 Newer alternative strategies for feeder-free, directed differentiation to NSCs utilizing chemical inhibitors and purified protein activators of specific signaling pathways important in fate determination have also been developed. 41, 42, 43 Further differentiation utilizing more specific cocktails of small molecules and purified protein for enrichment of neuronal subtypes such as dopaminergic populations has been applied to hiPSC studies in Parkinson's disease.…”

Section: Human-induced Pluripotent Stem Cells As a Tool To Address Somentioning

confidence: 99%

Implications and limitations of cellular reprogramming for psychiatric drug development

et al. 2013

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Human-induced pluripotent stem cells (hiPSCs) derived from somatic cells of patients have opened possibilities for in vitro modeling of the physiology of neural (and other) cells in psychiatric disease states. Issues in early stages of technology development include (1) establishing a library of cells from adequately phenotyped patients, (2) streamlining laborious, costly hiPSC derivation and characterization, (3) assessing whether mutations or other alterations introduced by reprogramming confound interpretation, (4) developing efficient differentiation strategies to relevant cell types, (5) identifying discernible cellular phenotypes meaningful for cyclic, stress induced or relapsing–remitting diseases, (6) converting phenotypes to screening assays suitable for genome-wide mechanistic studies or large collection compound testing and (7) controlling for variability in relation to disease specificity amidst low sample numbers. Coordination of material for reprogramming from patients well-characterized clinically, genetically and with neuroimaging are beginning, and initial studies have begun to identify cellular phenotypes. Finally, several psychiatric drugs have been found to alter reprogramming efficiency in vitro, suggesting further complexity in applying hiPSCs to psychiatric diseases or that some drugs influence neural differentiation moreso than generally recognized. Despite these challenges, studies utilizing hiPSCs may eventually serve to fill essential niches in the translational pipeline for the discovery of new therapeutics.

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Multiple layers of molecular controls modulate self-renewal and neuronal lineage specification of embryonic stem cells

Cited by 16 publications

References 80 publications

Identification ofin vivoDNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during forebrain and lens development

Identification ofin vivoDNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during forebrain and lens development

Fine-tuning of microRNA-mediated repression of mRNA by splicing-regulated and highly repressive microRNA recognition element

Implications and limitations of cellular reprogramming for psychiatric drug development

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