Let-7 represses Nr6a1 and a mid-gestation developmental program in adult fibroblasts [ChIP-seq_nr6a1]

MicroRNAs (miRNAs) are critical to proliferation, differentiation, and development. Here, we characterize gene expression in murine Dicer-null adult mesenchymal stem cell lines, a fibroblast cell type. Loss of Dicer leads to de-repression of let-7 targets at levels that exceed 10-100 fold with increases in transcription. Direct and indirect targets of this miRNA belong to a mid-gestation embryonic program that encompasses known oncofetal genes as well as oncogenes not previously associated with an embryonic state. Surprisingly, this mid-gestation program represents a distinct period that occurs between the pluripotent state of the inner cell mass at embryonic day 3.5 and the induction of let-7, upon differentiation, at embryonic day 10.5. Within this mid-gestation program, we characterize the let-7 target Nr6a1, an embryonic transcriptional repressor that regulates gene expression in adult fibroblasts following miRNA loss. In total, let-7 is required for the continual suppression of embryonic gene expression in adult cells, a mechanism that may underlie its tumor suppressive function.

微小RNA（MicroRNAs, miRNAs）在细胞增殖、分化与发育过程中发挥关键调控作用。本研究对小鼠Dicer基因敲除的成体间充质干细胞系（一种成纤维细胞类群）的基因表达特征进行了系统解析。研究发现，Dicer缺失可使let-7家族靶点的去抑制水平提升10至100倍，同时伴随转录水平上调。该miRNA的直接与间接调控靶点共同构成一套妊娠中期胚胎基因表达程序，其中既包含已报道的癌胚基因，也涵盖此前未被关联至胚胎发育状态的癌基因。令人意外的是，这套妊娠中期基因程序对应一段独特的发育窗口：其时间跨度介于胚胎发育第3.5天内细胞团的多能状态，与胚胎发育第10.5天分化诱导let-7表达的节点之间。在此妊娠中期基因程序中，我们还对let-7的调控靶点Nr6a1进行了系统表征，该基因作为胚胎转录抑制因子，可在miRNA缺失的成体成纤维细胞中调控基因表达。综上，let-7对于持续抑制成体细胞中的胚胎基因表达至关重要，这一机制或是其发挥抑癌功能的分子基础。