Epigenetic cues modulating the generation of cell‐type diversity in the cerebral cortex

Amberg, Nicole; Laukoter, Susanne; Hippenmeyer, Simon

doi:10.1111/jnc.14601

Cited by 21 publications

(20 citation statements)

References 145 publications

(292 reference statements)

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“…We thus sequenced a higher number of replicates and used SMARTer technology to remove potential bias from a varying number of cells present in each sample. We focused our analysis on chr7, because it carries a large number of imprinted genes, including some that have been shown to regulate cortical development ( Amberg et al., 2019 ; Perez et al., 2016 ; Tucci et al., 2019 ; Williamson et al., 2013 ). Upon RNA-seq, we performed principal-component analysis of the 64 samples ( Table S1 D) that passed quality control ( Figure 3 F).…”

Section: Resultsmentioning

confidence: 99%

“…The function of imprinted genes has been mainly studied using genetic full/global tissue KO ( Amberg et al., 2019 ; Perez et al., 2016 ; Tucci et al., 2019 ). However, the functional requirement of imprinted genes in single cells is mostly unknown.…”

Section: Discussionmentioning

confidence: 99%

“…The control of precise transcriptional programs establishing cortical cell fates includes epigenetic mechanisms ( Amberg et al., 2019 ). For instance, DNA methylation represents a critical epigenetic mark modifying DNA-protein interactions and thus controlling transcriptional states and cellular identity ( Albert et al., 2017 ; Gray et al., 2017 ; Luo et al., 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Cell-Type Specificity of Genomic Imprinting in Cerebral Cortex

Laukoter

Pauler

Beattie

et al. 2020

Neuron

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Summary In mammalian genomes, a subset of genes is regulated by genomic imprinting, resulting in silencing of one parental allele. Imprinting is essential for cerebral cortex development, but prevalence and functional impact in individual cells is unclear. Here, we determined allelic expression in cortical cell types and established a quantitative platform to interrogate imprinting in single cells. We created cells with uniparental chromosome disomy (UPD) containing two copies of either the maternal or the paternal chromosome; hence, imprinted genes will be 2-fold overexpressed or not expressed. By genetic labeling of UPD, we determined cellular phenotypes and transcriptional responses to deregulated imprinted gene expression at unprecedented single-cell resolution. We discovered an unexpected degree of cell-type specificity and a novel function of imprinting in the regulation of cortical astrocyte survival. More generally, our results suggest functional relevance of imprinted gene expression in glial astrocyte lineage and thus for generating cortical cell-type diversity.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cell-Type Specificity of Genomic Imprinting in Cerebral Cortex

Laukoter

Pauler

Beattie

et al. 2020

Neuron

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“…The genetic, molecular and cellular mechanisms that regulate RGP lineage progression and nascent projection neuron maturation are however not well understood. Furthermore, recent studies indicate that epigenetic regulatory cues at cellular and systemic levels play an important role as well 5,27 . One peculiar epigenetic regulatory mechanism is genomic imprinting, resulting in the selective silencing of one parental allele in a subset of genes [28][29][30] .…”

Section: Discussionmentioning

confidence: 99%

“…Impairments in neuron production and maturation lead to alterations in the cortical cytoarchitecture which is thought to represent the major underlying cause for a range of neurodevelopmental disorders including microcephaly, megalencephaly, epilepsy and autism spectrum disorders 4 . However, the cellular and molecular mechanisms that underlie concerted RGP lineage progression and the control of neuron output remain unclear 3,5,6 . Here we genetically dissect the ill-defined function of the essential Cdkn1c gene in corticogenesis.…”

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confidence: 99%

Imprinted Cdkn1c genomic locus cell-autonomously promotes cell survival in cerebral cortex development

et al. 2020

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The cyclin-dependent kinase inhibitor p57 KIP2 is encoded by the imprinted Cdkn1c locus, exhibits maternal expression, and is essential for cerebral cortex development. How Cdkn1c regulates corticogenesis is however not clear. To this end we employ Mosaic Analysis with Double Markers (MADM) technology to genetically dissect Cdkn1c gene function in corticogenesis at single cell resolution. We find that the previously described growth-inhibitory Cdkn1c function is a non-cell-autonomous one, acting on the whole organism. In contrast we reveal a growth-promoting cell-autonomous Cdkn1c function which at the mechanistic level mediates radial glial progenitor cell and nascent projection neuron survival. Strikingly, the growth-promoting function of Cdkn1c is highly dosage sensitive but not subject to genomic imprinting. Collectively, our results suggest that the Cdkn1c locus regulates cortical development through distinct cell-autonomous and non-cell-autonomous mechanisms. More generally, our study highlights the importance to probe the relative contributions of cell intrinsic gene function and tissue-wide mechanisms to the overall phenotype.

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The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

Mossink

Negwer

Schubert

et al. 2020

Cell. Mol. Life Sci.

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Neurodevelopmental disorders (NDDs), including intellectual disability (ID) and autism spectrum disorders (ASD), are a large group of disorders in which early insults during brain development result in a wide and heterogeneous spectrum of clinical diagnoses. Mutations in genes coding for chromatin remodelers are overrepresented in NDD cohorts, pointing towards epigenetics as a convergent pathogenic pathway between these disorders. In this review we detail the role of NDD-associated chromatin remodelers during the developmental continuum of progenitor expansion, differentiation, cell-type specification, migration and maturation. We discuss how defects in chromatin remodelling during these early developmental time points compound over time and result in impaired brain circuit establishment. In particular, we focus on their role in the three largest cell populations: glutamatergic neurons, GABAergic neurons, and glia cells. An in-depth understanding of the spatiotemporal role of chromatin remodelers during neurodevelopment can contribute to the identification of molecular targets for treatment strategies.

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Epigenetic cues modulating the generation of cell‐type diversity in the cerebral cortex

Cited by 21 publications

References 145 publications

Cell-Type Specificity of Genomic Imprinting in Cerebral Cortex

Cell-Type Specificity of Genomic Imprinting in Cerebral Cortex

Imprinted Cdkn1c genomic locus cell-autonomously promotes cell survival in cerebral cortex development

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

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