Differential genomic imprinting regulates paracrine and autocrine roles of IGF2 in mouse adult neurogenesis

Ferrón, Sacri R.; Radford, Elizabeth J.; Domingo-Muelas, Ana; Kleine, Iida-Marja; Ramme, Anja Patricia; Gray, Dionne; Sandovici, Ionel; Constância, Miguel; Ward, Andrew; Menheniott, Trevelyan R.; Ferguson-Smith, Anne C.

doi:10.1038/ncomms9265

Cited by 78 publications

(92 citation statements)

References 45 publications

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“…Genes in the Dlk1-Dio3 locus are highly expressed in the brain, an organ that was previously associated with complex parent-of-origin effects (Davies et al, 2005; Ferron et al, 2015; Perez et al, 2015; Sittig and Redei, 2014; Wilkinson et al, 2007; Xie et al, 2012). A recent report suggested that gain or loss of DNA methylation in the IG-DMR region may be regulated in a dynamic manner in the adult neurogenic niche (Ferron et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Parent-of-Origin DNA Methylation Dynamics during Mouse Development

Stelzer

Song

et al. 2016

Cell Reports

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Summary Parent-specific differentially methylated regions (DMRs) are established during gametogenesis and regulate parent-specific expression of imprinted genes. Monoallelic expression of imprinted genes is essential for development suggesting that imprints are faithfully maintained in embryo and adult. To test this hypothesis, we targeted a reporter for genomic methylation to the imprinted Dlk1-Dio3 intergenic DMR (IG-DMR) to assess the methylation of both parental alleles at single cell resolution. Biallelic gain or loss of IGDMR methylation occurred in a small fraction of mouse embryonic stem cells significantly affecting developmental potency. Mice carrying the reporter in either parental allele showed striking parent-specific changes in IG-DMR methylation causing substantial and consistent tissue- and cell type-dependent signatures in embryos and postnatal animals. Furthermore, dynamics in DNA methylation persisted during adult neurogenesis resulting in inter-individual diversity. This substantial cell-cell DNA methylation heterogeneity implies that dynamic DNA methylation variations in the adult may be of functional importance.

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Section: Discussionmentioning

confidence: 99%

Parent-of-Origin DNA Methylation Dynamics during Mouse Development

Stelzer

Song

et al. 2016

Cell Reports

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“…IGF2 and IGF1 receptor (IGF1R) signalling are thus emerging as key, context-dependent regulators of stem cell self-renewal and the proliferation of early progenitor cell pools in normal tissue architectures 62–64 , tumour tissues 59,60 and embryonic stem cell (ESC) cultures 65 . The properties of IGF2 in promoting stemness and tipping the balance between the stem/progenitor cell pool and differentiated progeny seems to be tightly connected with its role in cancer initiation and progression 57,59,60 .…”

Section: Epigenetic Mediatorsmentioning

confidence: 99%

Epigenetic modulators, modifiers and mediators in cancer aetiology and progression

2016

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This year is the tenth anniversary of the publication in this journal of a model suggesting the existence of ‘tumour progenitor genes’. These genes are epigenetically disrupted at the earliest stages of malignancies, even before mutations, and thus cause altered differentiation throughout tumour evolution. The past decade of discovery in cancer epigenetics has revealed a number of similarities between cancer genes and stem cell reprogramming genes, widespread mutations in epigenetic regulators, and the part played by chromatin structure in cellular plasticity in both development and cancer. In the light of these discoveries, we suggest here a framework for cancer epigenetics involving three types of genes: ‘epigenetic mediators’, corresponding to the tumour progenitor genes suggested earlier; ‘epigenetic modifiers’ of the mediators, which are frequently mutated in cancer; and ‘epigenetic modulators’ upstream of the modifiers, which are responsive to changes in the cellular environment and often linked to the nuclear architecture. We suggest that this classification is helpful in framing new diagnostic and therapeutic approaches to cancer.

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“…Interestingly, this paracrine mode of DLK1 signaling requires derepression of its maternal allele to achieve biallelic expression in both astrocytes and NSCs. Similarly, derepression of the Igf2 maternal allele to achieve biallelic expression in the SVZ is also required for NSC self-renewal postnatally, suggesting a remarkable mechanism of transcriptional dosage control in adult neurogenesis through imprinting regulation (Ferrón et al 2015). In the SGZ, the maternally expressed CDKN1C facilitates the maintenance of NSC quiescence (Furutachi et al 2013), and in contrast to the SVZ, IGF2 is paternally expressed and operates in an autocrine manner to regulate NSC survival (Bracko et al 2012, Ferrón et al 2015).…”

Section: Imprinted Genes and Epigenetic Control Of Neural Developmentmentioning

confidence: 99%

“…IGF2, which promotes adult neurogenesis (Bracko et al 2012, Ferrón et al 2015), is downregulated in animals exhibiting depression-like behavior after chronic stress (Luo et al 2014). Remarkably, overexpression of Igf2 in the dentate gyrus reverses these behaviors, but whether this effect is dependent on adult neurogenesis remains to be tested.…”

Section: Functions Of Imprinted Genes In the Postnatal Brainmentioning

confidence: 99%

New Perspectives on Genomic Imprinting, an Essential and Multifaceted Mode of Epigenetic Control in the Developing and Adult Brain

Pérez

Rubinstein²,

Dulac

2016

Annu. Rev. Neurosci.

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Mammalian evolution entailed multiple innovations in gene regulation, including the emergence of genomic imprinting, an epigenetic regulation leading to the preferential expression of a gene from its maternal or paternal allele. Genomic imprinting is highly prevalent in the brain, yet, until recently, its central roles in neural processes have not been fully appreciated. Here, we provide a comprehensive survey of adult and developmental brain functions influenced by imprinted genes, from neural development and wiring to synaptic function and plasticity, energy balance, social behaviors, emotions, and cognition. We further review the widespread identification of parental biases alongside monoallelic expression in brain tissues, discuss their potential roles in dosage regulation of key neural pathways, and suggest possible mechanisms underlying the dynamic regulation of imprinting in the brain. This review should help provide a better understanding of the significance of genomic imprinting in the normal and pathological brain of mammals including humans.

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Differential genomic imprinting regulates paracrine and autocrine roles of IGF2 in mouse adult neurogenesis

Cited by 78 publications

References 45 publications

Parent-of-Origin DNA Methylation Dynamics during Mouse Development

Parent-of-Origin DNA Methylation Dynamics during Mouse Development

Epigenetic modulators, modifiers and mediators in cancer aetiology and progression

New Perspectives on Genomic Imprinting, an Essential and Multifaceted Mode of Epigenetic Control in the Developing and Adult Brain

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