Regulation of neuronal commitment in mouse embryonic stem cells by the Reno1/Bahcc1 locus
Regulation of neuronal commitment in mouse embryonic stem cells by the Reno1/Bahcc1 locus
复制标题
DOI：
10.15252/embr.202051264
复制
发表时间：
2020-09-24
期刊：
影响因子：
7.7
通讯作者：
Ulitsky, Igor
中科院分区：
文献类型：
--
作者：
Hezroni, Hadas;Perry, Rotem B-T;Ulitsky, Igor
哺乳动物基因组编码数千个长非编码 RNA (lncRNA)，但其中大多数的生物学功能仍然未知。在哺乳动物大脑和早期胚胎中发现了特别丰富的 lncRNA 库。我们使用RNA-seq和计算分析来优先考虑lncRNA，这些lncRNA可能调节多能细胞对神经元命运的承诺，并在神经元分化之前扰乱它们的表达。通过 RNAi 敲除两种高度保守且表达良好的 lncRNA Reno1 (2810410L24Rik) 和 lnc-Nr2f1，可降低神经元标记物的表达，并导致分化细胞中基因表达的巨大变化。我们进一步表明，Reno1 基因座在神经发生过程中与其相邻的蛋白质编码基因 Bahcc1 形成越来越多的空间接触。 Reno1 或 Bahcc1 的缺失会导致神经元承诺早期停滞、无法诱导神经元基因表达程序，以及在分化开始时以 H3K4me3 染色质标记标记的区域染色质可及性整体降低。因此，Reno1 和 Bahcc1 形成了神经元承诺早期步骤所需的先前未表征的电路。
Mammalian genomes encode thousands of long noncoding RNAs (lncRNAs), yet the biological functions of most of them remain unknown. A particularly rich repertoire of lncRNAs found in mammalian brain and in the early embryo. We used RNA-seq and computational analysis to prioritize lncRNAs that may regulate commitment of pluripotent cells to a neuronal fate and perturbed their expression prior to neuronal differentiation. Knockdown by RNAi of two highly conserved and well-expressed lncRNAs, Reno1 (2810410L24Rik) and lnc-Nr2f1, decreased the expression of neuronal markers and led to massive changes in gene expression in the differentiated cells. We further show that the Reno1 locus forms increasing spatial contacts during neurogenesis with its adjacent protein-coding gene Bahcc1. Loss of either Reno1 or Bahcc1 leads to an early arrest in neuronal commitment, failure to induce a neuronal gene expression program, and to global reduction in chromatin accessibility at regions that are marked by the H3K4me3 chromatin mark at the onset of differentiation. Reno1 and Bahcc1 thus form a previously uncharacterized circuit required for the early steps of neuronal commitment.