Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
Cell. 2018 Jan 11;172(1-2):106-120.e21. doi: 10.1016/j.cell.2017.11.023. Epub 2017 Dec 14.
Cell fate transitions involve rapid gene expression changes and global chromatin remodeling, yet the underlying regulatory pathways remain incompletely understood. Here, we identified the RNA-processing factor Nudt21 as a novel regulator of cell fate change using transcription-factor-induced reprogramming as a screening assay. Suppression of Nudt21 enhanced the generation of induced pluripotent stem cells, facilitated transdifferentiation into trophoblast stem cells, and impaired differentiation of myeloid precursors and embryonic stem cells, suggesting a broader role for Nudt21 in cell fate change. We show that Nudt21 directs differential polyadenylation of over 1,500 transcripts in cells acquiring pluripotency, although only a fraction changed protein levels. Remarkably, these proteins were strongly enriched for chromatin regulators, and their suppression neutralized the effect of Nudt21 during reprogramming. Collectively, our data uncover Nudt21 as a novel post-transcriptional regulator of cell fate and establish a direct, previously unappreciated link between alternative polyadenylation and chromatin signaling.
细胞命运转变涉及快速的基因表达变化和全基因组染色质重塑，但潜在的调控途径仍不完全清楚。在这里，我们使用转录因子诱导的重编程作为筛选测定，将 RNA 处理因子 Nudt21 鉴定为细胞命运转变的新型调节剂。抑制 Nudt21 增强了诱导多能干细胞的生成，促进了滋养层干细胞的转分化，并损害了骨髓细胞前体和胚胎干细胞的分化，这表明 Nudt21 在细胞命运转变中具有更广泛的作用。我们表明，Nudt21 在细胞获得多能性时指导超过 1500 个转录本的差异聚腺苷酸化，尽管只有一部分改变了蛋白质水平。值得注意的是，这些蛋白质强烈富集染色质调节剂，并且它们的抑制在重编程过程中中和了 Nudt21 的作用。总的来说，我们的数据揭示了 Nudt21 是细胞命运的新型转录后调节剂，并在可变聚腺苷酸化和染色质信号之间建立了直接的、以前未被认识到的联系。
