Regeneration and tissue homeostasis require accurate production of missing cell lineages. Cell production is driven by changes to gene expression, which is shaped by multiple layers of regulation. Here, we find that the ubiquitous mRNA base-modification, m6A, is required for proper cell fate choice and cellular maturation in planarian stem cells (neoblasts). We mapped m6A-enriched regions in 7,600 planarian genes and found that perturbation of the m6A pathway resulted in progressive deterioration of tissues and death. Using single-cell RNA sequencing of >20,000 cells following perturbation of the m6A pathway, we identified an increase in expression of noncanonical histone variants, and that inhibition of the pathway resulted in accumulation of undifferentiated cells throughout the animal in an abnormal transcriptional state. Analysis of >1,000 planarian gene expression datasets revealed that the inhibition of the chromatin modifying complex NuRD had almost indistinguishable consequences, unraveling an unappreciated link between m6A and chromatin modifications. Our findings reveal that m6A is critical for planarian stem cell homeostasis and gene regulation in tissue maintenance and regeneration.

中文翻译：

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m6A 是涡虫干细胞分化过程中解决祖细胞身份所必需的

再生和组织稳态需要准确生成缺失的细胞谱系。细胞生产是由基因表达的变化驱动的，而基因表达的变化又受到多层调控的影响。在这里，我们发现无处不在的 mRNA 碱基修饰 m6A 是涡虫干细胞（新生细胞）中正确的细胞命运选择和细胞成熟所必需的。我们绘制了 7,600 个涡虫基因中富含 m6A 的区域，发现 m6A 通路的扰动会导致组织进行性恶化和死亡。通过对 m6A 通路扰动后超过 20,000 个细胞进行单细胞 RNA 测序，我们发现非经典组蛋白变体的表达增加，并且该通路的抑制导致未分化细胞在整个动物体内积累，处于异常转录状态。分析 >1, 000 涡虫基因表达数据集显示，染色质修饰复合物 NuRD 的抑制具有几乎无法区分的后果，揭示了 m6A 和染色质修饰之间未被重视的联系。我们的研究结果表明，m6A 对于涡虫干细胞稳态以及组织维持和再生中的基因调控至关重要。