Experimental Cardiology Unit, Department of Cardiovascular Medicine, University of Lausanne Medical School, 1011, Lausanne, Switzerland.
Neuroinfectiology Laboratory, Institute for Infectious Diseases, University of Bern, 3001, Bern, Switzerland.
Nat Commun. 2017 Nov 27;8(1):1806. doi: 10.1038/s41467-017-01804-w.
Enhancers and long noncoding RNAs (lncRNAs) are key determinants of lineage specification during development. Here, we evaluate remodeling of the enhancer landscape and modulation of the lncRNA transcriptome during mesendoderm specification. We sort mesendodermal progenitors from differentiating embryonic stem cells (ESCs) according to Eomes expression, and find that enhancer usage is coordinated with mesendoderm-specific expression of key lineage-determining transcription factors. Many of these enhancers are associated with the expression of lncRNAs. Examination of ESC-specific enhancers interacting in three-dimensional space with mesendoderm-specifying transcription factor loci identifies MesEndoderm Transcriptional Enhancer Organizing Region (Meteor). Genetic and epigenetic manipulation of the Meteor enhancer reveal its indispensable role during mesendoderm specification and subsequent cardiogenic differentiation via transcription-independent and -dependent mechanisms. Interestingly, Meteor-deleted ESCs are epigenetically redirected towards neuroectodermal lineages. Loci, topologically associating a transcribed enhancer and its cognate protein coding gene, appear to represent therefore a class of genomic elements controlling developmental competence in pluripotency.
增强子和长非编码 RNA（lncRNA）是发育过程中谱系特化的关键决定因素。在这里，我们评估了中胚层特化过程中增强子景观的重塑和 lncRNA 转录组的调节。我们根据 Eomes 的表达从分化的胚胎干细胞（ESCs）中分拣中胚层祖细胞，发现增强子的使用与关键谱系决定转录因子的中胚层特异性表达协调一致。其中许多增强子与 lncRNA 的表达相关。检查与中胚层指定转录因子基因座在三维空间中相互作用的 ESC 特异性增强子，鉴定出 MesEndoderm Transcriptional Enhancer Organizing Region（Meteor）。通过转录独立和依赖机制，对 Meteor 增强子进行遗传和表观遗传操作，揭示了其在中胚层特化和随后的心源性分化过程中的不可或缺的作用。有趣的是，Meteor 缺失的 ESCs 在表观遗传上被重新定向到神经外胚层谱系。因此，拓扑关联转录增强子和其同源蛋白编码基因的基因座似乎代表了一类控制多能性中发育能力的基因组元件。
