Paupar LncRNA Promotes KAP1 Dependent Chromatin Changes And Regulates Subventricular Zone Neurogenesis
Paupar LncRNA Promotes KAP1 Dependent Chromatin Changes And Regulates Subventricular Zone Neurogenesis
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DOI：
10.1101/187302
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发表时间：
2017-09
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影响因子：
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通讯作者：
Ioanna Pavlaki;Farah Alammari;Bin Sun;N. Clark;T. Sirey;Sheena Lee;D. Woodcock;C. Ponting;F. Szele;Keith W. Vance
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文献类型：
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作者：
Ioanna Pavlaki;Farah Alammari;Bin Sun;N. Clark;T. Sirey;Sheena Lee;D. Woodcock;C. Ponting;F. Szele;Keith W. Vance
许多长链非编码RNA（lncRNA）在中枢神经系统（CNS）发育过程中表达，但其在体内的作用和分子作用机制仍知之甚少。Paupar是一种CNS表达的lncRNA，通过结合和调节全基因组转录调控元件的活性来控制神经母细胞瘤细胞的生长。我们在这里表明，Paupar转录直接结合KAP 1，一个重要的表观遗传调控蛋白，从而调节共同的靶基因的表达，重要的增殖和神经元分化。Paupar通过形成含有Paupar、KAP 1和PAX 6转录因子的DNA结合核糖核蛋白复合物，促进KAP 1染色质占据和H3 K9 me 3在远端靶点的亚组沉积。Paupar-KAP 1全基因组共占有揭示了Paupar和KAP 1结合序列之间重叠的4倍富集。此外，Paupar和Kap 1在体内的功能丧失加速了小鼠出生后脑室下区（SVZ）干细胞龛的谱系进展，并破坏了嗅球神经发生。这些观察结果为lncRNA介导的表观遗传调控的反式作用模式、KAP 1基因组募集机制提供了重要的概念性见解，并确定了Paupar和Kap 1作为SVZ神经发生的调节因子。
Many long non-coding RNAs (lncRNAs) are expressed during central nervous system (CNS) development, yet their in vivo roles and molecular mechanisms of action remain poorly understood. Paupar, a CNS expressed lncRNA, controls neuroblastoma cell growth by binding and modulating the activity of genome-wide transcriptional regulatory elements. We show here that Paupar transcript directly binds KAP1, an essential epigenetic regulatory protein, and thereby regulates the expression of shared target genes important for proliferation and neuronal differentiation. Paupar promotes KAP1 chromatin occupancy and H3K9me3 deposition at a subset of distal targets, through formation of a DNA binding ribonucleoprotein complex containing Paupar, KAP1 and the PAX6 transcription factor. Paupar-KAP1 genome-wide co-occupancy reveals a 4-fold enrichment of overlap between Paupar and KAP1 bound sequences. Furthermore, both Paupar and Kap1 loss of function in vivo accelerates lineage progression in the mouse postnatal subventricular zone (SVZ) stem cell niche and disrupts olfactory bulb neurogenesis. These observations provide important conceptual insights into the trans-acting modes of lncRNA-mediated epigenetic regulation, the mechanisms of KAP1 genomic recruitment and identify Paupar and Kap1 as regulators of SVZ neurogenesis.