In Vitro Corticogenesis from Embryonic Stem Cells Recapitulates the In Vivo Epigenetic Control of Imprinted Gene Expression.
In vitro corticogenesis from embryonic stem cells (ESCs) is an attractive model of cortical development and a promising tool for cortical therapy. It is unknown to which extent epigenetic mechanisms crucial for cortex development and function, such as parental genomic imprinting, are recapitulated by in vitro corticogenesis. Here, using genome-wide transcriptomic and methylation analyses on hybrid mouse tissues and cells, we find a high concordance of imprinting status between in vivo and ESC-derived cortices. Notably, in vitro corticogenesis strictly reproduced the in vivo parent-of-origin-dependent expression of 41 imprinted genes (IGs), including Mest and Cdkn1c known to control corticogenesis. Parent-of-origin-dependent DNA methylation was also conserved at 14 of 18 imprinted differentially methylated regions. The least concordant imprinted locus was Gpr1-Zdbf2, where the aberrant bi-allelic expression of Zdbf2 and Adam23 was concomitant with a gain of methylation on the maternal allele in vitro. Combined, our data argue for a broad conservation of the epigenetic mechanisms at imprinted loci in cortical cells derived from ESCs. We propose that in vitro corticogenesis helps to define the still poorly understood mechanisms that regulate imprinting in the brain and the roles of IGs in cortical development.
Institut de Génomique Fonctionnelle (IGF), CNRS UMR5203, INSERM U1191, Université de Montpellier, Montpellier, France.
Tristan
T
Bouschet
Montpellier GenomiX, BioCampus Montpellier, CNRS UMS3426, INSERM US009, Université de Montpellier, Montpellier, France.
Emeric
E
Dubois
Institut de Génomique Fonctionnelle (IGF), CNRS UMR5203, INSERM U1191, Université de Montpellier, Montpellier, France.
Christelle
C
Reynès
Institute of Molecular Genetics (IGMM), CNRS UMR 5535, University of Montpellier, Montpellier, France.
Satya K
SK
Kota
Montpellier GenomiX, BioCampus Montpellier, CNRS UMS3426, INSERM US009, Université de Montpellier, Montpellier, France.
Stéphanie
S
Rialle
GReD (Genetics, Reproduction and Development), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France.
Stéphanie
S
Maupetit-Méhouas
Institut de Génomique Fonctionnelle (IGF), CNRS UMR5203, INSERM U1191, Université de Montpellier, Montpellier, France.
Mikael
M
Pezet
Institut de Génomique Fonctionnelle (IGF), CNRS UMR5203, INSERM U1191, Université de Montpellier, Montpellier, France.
Anne
A
Le Digarcher
Montpellier GenomiX, BioCampus Montpellier, CNRS UMS3426, INSERM US009, Université de Montpellier, Montpellier, France.
Sabine
S
Nidelet
Montpellier GenomiX, BioCampus Montpellier, CNRS UMS3426, INSERM US009, Université de Montpellier, Montpellier, France.
Vincent
V
Demolombe
Institute of Molecular Genetics (IGMM), CNRS UMR 5535, University of Montpellier, Montpellier, France.
Patricia
P
Cavelier
Institut de Génomique Fonctionnelle (IGF), CNRS UMR5203, INSERM U1191, Université de Montpellier, Montpellier, France.
Céline
C
Meusnier
Institut de Génomique Fonctionnelle (IGF), CNRS UMR5203, INSERM U1191, Université de Montpellier, Montpellier, France.|Institute of Molecular Genetics (IGMM), CNRS UMR 5535, University of Montpellier, Montpellier, France.
Chloé
C
Maurizy
Institut de Génomique Fonctionnelle (IGF), CNRS UMR5203, INSERM U1191, Université de Montpellier, Montpellier, France.
Robert
R
Sabatier
Institute of Molecular Genetics (IGMM), CNRS UMR 5535, University of Montpellier, Montpellier, France.
Robert
R
Feil
GReD (Genetics, Reproduction and Development), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France.
Philippe
P
Arnaud
Institut de Génomique Fonctionnelle (IGF), CNRS UMR5203, INSERM U1191, Université de Montpellier, Montpellier, France.|Montpellier GenomiX, BioCampus Montpellier, CNRS UMS3426, INSERM US009, Université de Montpellier, Montpellier, France.
Laurent
L
Journot
Institut de Génomique Fonctionnelle (IGF), CNRS UMR5203, INSERM U1191, Université de Montpellier, Montpellier, France.
Annie
A
Varrault
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology; D002540:Cerebral Cortex / Q000254:growth & development* / Q000378:metabolism*; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental; D056426:Genetic Loci; D018392:Genomic Imprinting; D051379:Mice; D008856:Microscopy, Fluorescence; D058953:Neural Stem Cells / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome
DNA methylation; allele-specific expression; corticogenesis; embryonic stem cells; genomic imprinting