PDF(Pubmed)
Abstract：
Coordination of neuronal differentiation with expansion of the neuroepithelial/neural progenitor cell (NEPC/NPC) pool is essential in early brain development. Our in vitro and in vivo studies identify independent and opposing roles for two neural-specific and differentially expressed non-coding RNAs derived from the same locus: the evolutionarily conserved lncRNA Rncr3 and the embedded microRNA miR124a-1. Rncr3 regulates NEPC/NPC proliferation and controls the biogenesis of miR124a, which determines neuronal differentiation. Rncr3 conserved exons 2/3 are cytosine methylated and bound by methyl-CpG binding protein MeCP2, which restricts expression of miR124a embedded in exon 4 to prevent premature neuronal differentiation, and to orchestrate proper brain growth. MeCP2 directly binds cytosine-methylated Rncr3 through previously unrecognized lysine residues and suppresses miR124a processing by recruiting PTBP1 to block access of DROSHA-DGCR8. Thus, miRNA processing is controlled by lncRNA m5C methylation along with the defined m5C epitranscriptomic RNA reader protein MeCP2 to coordinate brain development.
摘要：
神经元分化与神经上皮/神经祖细胞（NEPC/NPC）池扩增的协调在早期脑发育中至关重要。我们的体外和体内研究确定了来自同一基因座的两种神经特异性和差异表达的非编码RNA的独立和相反的作用：进化上保守的lncRNARncr3和嵌入的microRNAmiR124a-1。Rncr3调节NEPC/NPC增殖并控制miR124a的生物发生，决定神经元分化。Rncr3保守的外显子2/3被胞嘧啶甲基化并被甲基-CpG结合蛋白MeCP2结合，这限制了嵌入外显子4中的miR124a的表达，以防止过早的神经元分化，并协调适当的大脑生长。MeCP2通过先前未识别的赖氨酸残基直接结合胞嘧啶甲基化的Rncr3，并通过募集PTBP1以阻断DROSHA-DGCR8的访问来抑制miR124a加工。因此，miRNA加工受lncRNAm5C甲基化以及定义的m5C表位基因组RNA阅读器蛋白MeCP2控制，以协调大脑发育。
