Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.
Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA.
Nat Commun. 2016 Jul 5;7:12143. doi: 10.1038/ncomms12143.
The RNA-binding protein (RBP) TAF15 is implicated in amyotrophic lateral sclerosis (ALS). To compare TAF15 function to that of two ALS-associated RBPs, FUS and TDP-43, we integrate CLIP-seq and RNA Bind-N-Seq technologies, and show that TAF15 binds to ∼4,900 RNAs enriched for GGUA motifs in adult mouse brains. TAF15 and FUS exhibit similar binding patterns in introns, are enriched in 3' untranslated regions and alter genes distinct from TDP-43. However, unlike FUS and TDP-43, TAF15 has a minimal role in alternative splicing. In human neural progenitors, TAF15 and FUS affect turnover of their RNA targets. In human stem cell-derived motor neurons, the RNA profile associated with concomitant loss of both TAF15 and FUS resembles that observed in the presence of the ALS-associated mutation FUS R521G, but contrasts with late-stage sporadic ALS patients. Taken together, our findings reveal convergent and divergent roles for FUS, TAF15 and TDP-43 in RNA metabolism.
RNA 结合蛋白（RBP）TAF15 与肌萎缩侧索硬化症（ALS）有关。为了比较 TAF15 与两种与 ALS 相关的 RBP（FUS 和 TDP-43）的功能，我们整合了 CLIP-seq 和 RNA Bind-N-Seq 技术，并表明 TAF15 结合了约 4900 种富含 GGUA 基序的 RNA，这些 RNA 在成年小鼠大脑中富集。TAF15 和 FUS 在内含子中表现出相似的结合模式，在 3'非翻译区富集，并改变与 TDP-43 不同的基因。然而，与 FUS 和 TDP-43 不同，TAF15 在可变剪接中作用很小。在人类神经祖细胞中，TAF15 和 FUS 影响其 RNA 靶标的周转。在人类干细胞衍生的运动神经元中，与同时丧失 TAF15 和 FUS 相关的 RNA 谱与观察到的 ALS 相关突变 FUS R521G 存在时的 RNA 谱相似，但与晚期散发性 ALS 患者的 RNA 谱形成对比。总之，我们的研究结果揭示了 FUS、TAF15 和 TDP-43 在 RNA 代谢中的趋同和发散作用。
