Bouschet Tristan, Dubois Emeric, Reynès Christelle, Kota Satya K, Rialle Stéphanie, Maupetit-Méhouas Stéphanie, Pezet Mikael, Le Digarcher Anne, Nidelet Sabine, Demolombe Vincent, Cavelier Patricia, Meusnier Céline, Maurizy Chloé, Sabatier Robert, Feil Robert, Arnaud Philippe, Journot Laurent, Varrault Annie
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.
Cereb Cortex. 2017 Mar 1;27(3):2418-2433. doi: 10.1093/cercor/bhw102.
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.
胚胎干细胞（ESC）的体外皮质发生是一种引人注目的皮质发育模型，也是一种有前景的皮质治疗工具。目前尚不清楚对皮质发育和功能至关重要的表观遗传机制，如亲本基因组印记，在多大程度上能被体外皮质发生所重现。在此，我们对杂交小鼠组织和细胞进行全基因组转录组和甲基化分析，发现体内和ESC来源的皮质之间印记状态高度一致。值得注意的是，体外皮质发生严格重现了41个印记基因（IG）在体内依赖亲本来源的表达，包括已知控制皮质发生的Mest和Cdkn1c。在18个印记差异甲基化区域中的14个区域，亲本来源依赖的DNA甲基化也得以保留。一致性最低的印记位点是Gpr1-Zdbf2，在体外，Zdbf2和Adam23的异常双等位基因表达与母本等位基因甲基化增加同时出现。综合来看，我们的数据表明ESC来源的皮质细胞中印迹位点的表观遗传机制具有广泛的保守性。我们认为，体外皮质发生有助于明确仍知之甚少的调节大脑印记的机制以及IG在皮质发育中的作用。
