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Embryonic stem cell-derived cerebral cortex largely reproduces the in vivo epigenetic control of imprinted gene expression [RNA-seq]

ABSTRACT: In vitro differentiation of embryonic stem cells (ESC) provides models that reproduce in vivo development and cells for therapy. Whether the epigenetic signatures that are crucial for brain development and function and that are sensitive to in vitro culture are similar between native brain tissues and their artificial counterpart generated from ESC is largely unknown. Here, using RNA-seq we have compared the parental origin-dependent expression of imprinted genes (IGs), a model of epigenetic regulation, in cerebral cortex generated either in vivo, or from ESCs using in vitro corticogenesis, a model that reproduces the landmarks of in vivo corticogenesis. For a majority of IGs, the expressed parental alleles were the same for in vivo and in vitro cortex. In most cases, this choice was already set in ESCs and faithfully maintained during the 3 weeks of in vitro corticogenesis. Confirming these findings, methylation, which selects the parental allele to be transcribed, was also largely equivalent between the 2 types of cortex and ESCs. Our results thus indicate that the allele specific expression of imprinted transcripts, a model of epigenetic regulation resulting from a differential methylation of parental genomes, is mostly mimicked in cortical cells derived from ESC.

ORGANISM(S): Mus musculus

PROVIDER: GSE58523 | GEO | 2016/04/21

SECONDARY ACCESSION(S): PRJNA252829

REPOSITORIES: GEO

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Conservation of parental genomic imprinting by cortex generated from embryonic stem cells [RRBS-seq]

Project description:In vitro cortex generated from embryonic stem cells (ESCs) is a model system to investigate corticogenesis and a promising tool for cortical therapy. A fundamental question that has implications for understanding corticogenesis and for using stem cells therapeutically is to determine whether in vitro cortex reproduces some fine-tuned epigenetic modifications that are important for corticogenesis and function in vivo such as parent-of-origin dependent DNA methylation and expression of imprinted genes (IGs). Here, we have compared at single-base resolution the parent-of-origin dependent DNA methylation and expression of IGs in hybrid cortices generated either in vivo or in vitro from ESCs using Reduced Representation Bisulfite Sequencing (RRBS) and RNA-seq. We report that in vitro cortex strictly reproduced the in vivo parental expression of 41 IGs, including those involved in corticogenesis such as Mest (paternal) and Cdkn1c (maternal). The expressed allele was set in ESCs and maintained during in vitro corticogenesis for most IGs but some switched from a biallelic expression in ESCs to the monoallelic expression observed in vivo. RRBS experiments revealed that parent-of-origin dependent methylation at imprinted loci were also largely similar in in vitro and in vivo cortices except at a few loci. The most discordant locus was Gpr1-Zdbf2: Zdbf2 RNA was paternal in vivo and biallelic in vitro, and this was concomitant with an aberrant gain of methylation on the maternal allele in vitro. Thus, we conclude that the epigenetic mechanisms at imprinted loci are largely but not strictly preserved in vitro. We propose that in vitro corticogenesis, with its set of IGs displaying faithful parent-of-origin dependent expression and methylation, helps to define the poorly known mechanisms regulating imprinting in the brain and roles of IGs during corticogenesis.

2016-04-21 | GSE75485 | GEO

MicroRNA expression in a model of mouse corticogenesis

Project description:We established an in vitro model of mouse corticogenesis starting from mouse embryonic stem cells (ESCs). We analyzed miRNAomes of dividing and post-mitotic ESC-cortical cells and miRNAomes of E12 and P0 mouse cortex. By comparing the microRNA expression profiles of progenitors and precursors at different times of in vitro differentiation to the microRNA expression profiles of E12 and P0 mouse cortex we validated the model of mouse in vitro corticogenesis and provided microRNA expression datasets of early mouse embryonic cerebral cortex. Moreover, by the miR-CATCH method we analyzed the enrichement of microRNAs after the binding to the 3’UTR of Satb2. This allowed to identify microRNAs that directly inhibit SATB2 expression.

2021-04-22 | GSE172502 | GEO

Coding mutations and loss-of-imprinting in human pluripotent cells derived by nuclear transfer and defined factors [RNA-Seq]

Project description:Human pluripotent stem cells can be derived from somatic cells by forced expression of defined factors, and more recently by nuclear-transfer into human oocytes, revitalizing a debate on whether one reprogramming approach might be advantageous over the other. Here we compared the genetic and epigenetic stability of human nuclear-transfer embryonic stem cell (NT-ESC) lines and isogenic induced pluripotent stem cell (iPSC) lines, derived from the same somatic cell cultures of fetal, neonatal and adult origin. Both cell types shared similar genome-wide gene expression and DNA methylation profiles. Importantly, NT-ESCs and iPSCs have comparable numbers of de novo coding mutations but significantly higher than parthenogenetic ESCs. Similar to iPSCs NT-ESCs displayed clone- and gene-specific aberrations in DNA methylation and allele-specific expression of imprinted genes, similarly to iPSCs. The occurrence of these genetic and epigenetic defects in both NT-ESCs and iPSCs suggests that they are inherent to reprogramming, regardless of the underlying technique. RNA sequencing analysis was performed on a total of 12 human cell lines, including: an isogenic set of 3 nuclear-transfer embryonic stem cell (NT-ESC) lines, 2 RNA-reprogrammed induced pluripotent stem cell (iPSC) lines and their parental neonatal fibroblast cell line; an isogenic set of 1 NT-ESC line, 3 iPSC lines and their parental adult fibroblast cell line (derived from a type 1 diabetic subject); as well as 1 control embryonic stem cell (ESC) line.

2014-11-06 | E-GEOD-61656 | biostudies-arrayexpress

Coding mutations and loss-of-imprinting in human pluripotent cells derived by nuclear transfer and defined factors [DNA methylation profiling]

Project description:Human pluripotent stem cells can be derived from somatic cells by forced expression of defined factors, and more recently by nuclear-transfer into human oocytes, revitalizing a debate on whether one reprogramming approach might be advantageous over the other. Here we compared the genetic and epigenetic stability of human nuclear-transfer embryonic stem cell (NT-ESC) lines and isogenic induced pluripotent stem cell (iPSC) lines, derived from the same somatic cell cultures of fetal, neonatal and adult origin. Both cell types shared similar genome-wide gene expression and DNA methylation profiles. Importantly, NT-ESCs and iPSCs have comparable numbers of de novo coding mutations but significantly higher than parthenogenetic ESCs. Similar to iPSCs NT-ESCs displayed clone- and gene-specific aberrations in DNA methylation and allele-specific expression of imprinted genes, similarly to iPSCs. The occurrence of these genetic and epigenetic defects in both NT-ESCs and iPSCs suggests that they are inherent to reprogramming, regardless of the underlying technique. Genome-wide DNA methylation profiling by Illumina Infinium HumanMethylation 450K Beadchip was performed on a total of 21 human cell lines, including: an isogenic set of 3 nuclear-transfer embryonic stem cell (NT-ESC) lines, 2 RNA-reprogrammed induced pluripotent stem cell (iPSC) lines and their parental neonatal fibroblast cell line; an isogenic set of 1 NT-ESC line, 6 iPSC lines and their parental adult fibroblast cell line (derived from a type 1 diabetic subject); as well as 7 control embryonic stem cell (ESC) lines.

2014-11-06 | E-GEOD-61461 | biostudies-arrayexpress

A mass spectrometry survey of chromatin-associated proteins in pluripotency and early lineage commitment

Project description:Pluripotent Embryonic Stem Cells (ESCs) can be captured in vitro in different states, ranging from unrestricted ‘naïve’ to more developmentally constrained ‘primed’ pluripotency. Complexes involved in epigenetic regulation and key transcription factors have been shown to be involved in specifying these distinct states. In this study, we use proteomic profiling of the chromatin landscape in naive pluripotent ESCs, Epistem cells (EpiSCs) and early differentiated ESCs to survey the chromatin in naïve and primed pluripotency and during differentiation. We provide a comprehensive overview of epigenetic complexes situated on the chromatin and identify proteins associated with the maintenance and loss of pluripotency. The findings presented here indicate major compositional alterations of epigenetic complexes starting from ESC priming onwards. Our results contribute to the understanding of ESC differentiation and provide a framework for future studies of lineage commitment of ESCs.

2019-07-04 | PXD011782 | Pride

Distinct imprinting signatures and biased differentiation of human androgenetic and parthenogenetic embryonic stem cells [microarray]

Project description:Genomic imprinting is an epigenetic mechanism that results in parent-of-origin monoallelic expression of specific genes, which precludes uniparental development and underlies various diseases. Here we explored molecular and developmental aspects of imprinting in humans by generating exclusively-paternal human androgenetic embryonic stem cells (aESCs) and comparing them with exclusively-maternal parthenogenetic ESCs (pESCs) and bi-parental ESCs, establishing a pluripotent-cell system of distinct parental backgrounds. Analyzing the transcriptomes and methylomes of human aESCs, pESCs and bi-parental ESCs enabled the characterization of regulatory relations at known imprinted regions and uncovered new imprinted gene candidates within and outside known imprinted regions. Investigating the consequences of uniparental differentiation, we showed the known paternal-genome preference for placental contribution, revealed a novel bias towards liver differentiation, and implicated the involvement of the imprinted gene IGF2 in this process. Our results demonstrate the utility of parent-specific human ESCs for dissecting the role of imprinting in human development and disease.

2019-09-05 | GSE114676 | GEO

Distinct imprinting signatures and biased differentiation of human androgenetic and parthenogenetic embryonic stem cells [RNA-Seq II]

Project description:Genomic imprinting is an epigenetic mechanism that results in parent-of-origin monoallelic expression of specific genes, which precludes uniparental development and underlies various diseases. Here, we explored molecular and developmental aspects of imprinting in humans by generating exclusively paternal human androgenetic embryonic stem cells (aESCs) and comparing them with exclusively maternal parthenogenetic ESCs (pESCs) and bi-parental ESCs, establishing a pluripotent cell system of distinct parental backgrounds. Analyzing the transcriptomes and methylomes of human aESCs, pESCs, and bi-parental ESCs enabled the characterization of regulatory relations at known imprinted regions and uncovered imprinted gene candidates within and outside known imprinted regions. Investigating the consequences of uniparental differentiation, we showed the known paternal-genome preference for placental contribution, revealed a similar bias toward liver differentiation, and implicated the involvement of the imprinted gene IGF2 in this process. Our results demonstrate the utility of parent-specific human ESCs for dissecting the role of imprinting in human development and disease.

2019-09-05 | GSE114677 | GEO

Distinct imprinting signatures and biased differentiation of human androgenetic and parthenogenetic embryonic stem cells [RNA-Seq I]

Project description:Genomic imprinting is an epigenetic mechanism that results in parent-of-origin monoallelic expression of specific genes, which precludes uniparental development and underlies various diseases. Here, we explored molecular and developmental aspects of imprinting in humans by generating exclusively paternal human androgenetic embryonic stem cells (aESCs) and comparing them with exclusively maternal parthenogenetic ESCs (pESCs) and bi-parental ESCs, establishing a pluripotent cell system of distinct parental backgrounds. Analyzing the transcriptomes and methylomes of human aESCs, pESCs, and bi-parental ESCs enabled the characterization of regulatory relations at known imprinted regions and uncovered imprinted gene candidates within and outside known imprinted regions. Investigating the consequences of uniparental differentiation, we showed the known paternal-genome preference for placental contribution, revealed a similar bias toward liver differentiation, and implicated the involvement of the imprinted gene IGF2 in this process. Our results demonstrate the utility of parent-specific human ESCs for dissecting the role of imprinting in human development and disease.

2019-09-05 | GSE114678 | GEO

Integrative proteomics reveals a protective role of PRC2 for the ground state pluripotent epigenome

Project description:The ground state of pluripotency is defined as a basal proliferative state free of epigenetic restriction, represented by mouse embryonic stem cells (ESCs) cultured with two kinase inhibitors (so-called “2i”). Through comparison with serum-grown ESCs, we identify epigenetic features characterizing 2i ESCs by proteome profiling of chromatin including post-translational histone modifications. The most prominent difference is H3K27me3 and its enzymatic writer complex PRC2 that are highly abundant on eu- and heterochromatin in 2i ESCs, with H3K27me3 redistributing outside canonical PRC2 targets in a CpG-dependent fashion. Using PRC2-deficient 2i ESCs, we identify epigenetic crosstalk with H3K27me3, including significant increases in H4 acetylation and DNA methylation. This suggests that the unique H3K27me3 configuration protects 2i ESCs from preparation to lineage priming. Interestingly, removal of DNA methylation in PRC2-deficient 2i ESCs lacking H3K27me3 using 5-azacytidine hardly affected ESC viability and transcriptome, showing that ESCs are independent of both major repressive epigenetic marks.

2018-11-21 | PXD007154 | Pride

Transcriptome profiling of miR-541 kd mouse cortical cells

Project description:Using an in vitro model of mouse corticogenesis from mouse embryonic stem cells (ESCs), we investigated the gene expression changes exerted by the inactivation of the Eutherian-specific microRNA miR-541. The microRNA mmu-miR-541-5p was inhibited by the transfection of an antago-miR into ESC-progenitors at 12 days of in vitro differentiation (DIV12) and and the cell transcriptome of transfected cells was compared to the transcriptome of control-transfected cells 5 days after transfection (DIV17). The comparison between control and miR-541 kd cells highlighted classes of differentially expressed genes related to axon elongation and neural development GO terms.

2021-04-22 | GSE172503 | GEO

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