Coordinated control of mRNA and rRNA processing regulates early mammalian embryogenesis [ChIP-Seq_PolII]

Stem cells are regulated by transcriptional networks controlling pluripotency and differentiation. How basic cellular processes like splicing or protein synthesis regulate stem cell function is less well understood. Here, we show that the RNA binding protein HTATSF1 controls protein synthesis by controlling several independent RNA processing steps during ribosome biogenesis. In a complex with ribosomal RNA transcription and processing factors, HTATSF1 regulates ribosomal RNA abundance. By binding to the U2snRNP complex, HTATSF1 also controls intron removal specifically in ribosomal protein transcripts. HTATSF1-mediated control of protein synthesis is essential for the transition from the naïve pre-implantation epiblast to the primed post-implantation epiblast, a stage of low protein synthesis levels, and during further differentiation towards neuroectoderm. Our results identify coordinated regulation of ribosomal RNA and protein biosynthesis by HTATSF1 as an essential mechanism to mediate protein synthesis control during early stages of mammalian embryogenesis.

干细胞的命运由调控多能性与分化过程的转录网络所调控。诸如剪接或蛋白质合成这类基础细胞过程如何调控干细胞功能，目前尚未得到充分阐释。本研究发现，RNA结合蛋白HTATSF1可通过调控核糖体生物发生过程中的多个独立RNA加工步骤，实现对蛋白质合成的调控。HTATSF1与核糖体RNA转录及加工因子形成复合物，可调控核糖体RNA的丰度；同时通过结合U2小核糖核蛋白（U2snRNP）复合物，HTATSF1还可特异性调控核糖体蛋白转录本的内含子切除。HTATSF1介导的蛋白质合成调控，对于幼稚型植入前上胚层向启动型植入后上胚层的转变（该阶段蛋白质合成水平较低），以及后续向神经外胚层的分化过程均至关重要。本研究结果证实，HTATSF1对核糖体RNA及蛋白质生物合成的协同调控，是哺乳动物胚胎发育早期阶段介导蛋白质合成调控的核心机制。