Opposing Roles for the lncRNA Haunt and Its Genomic Locus in Regulating HOXA Gene Activation during Embryonic Stem Cell Differentiation
Opposing Roles for the lncRNA Haunt and Its Genomic Locus in Regulating HOXA Gene Activation during Embryonic Stem Cell Differentiation
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DOI：
10.1016/j.stem.2015.03.007
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发表时间：
2015-05-07
期刊：
影响因子：
23.9
通讯作者：
Shen, Xiaohua
中科院分区：
文献类型：
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作者：
Yin, Yafei;Yan, Pixi;Shen, Xiaohua
长非编码RNA(Long Non Coding RNAs，LncRNAs)参与控制胚胎干细胞(ESC)生物学的各个方面，但其功能及其作用的分子机制尚不清楚。在这里，我们展示了在胚胎干细胞分化过程中，lncRNA转录困扰及其基因组位置在调节HOXA基因簇中的离散和相反的作用。减少或增强Hoxa基因的表达，在对Hoxa基因的干扰最小的情况下，分别导致Hoxa基因的上调或下调。相反，出没基因座内越来越大的基因组缺失减弱了Hoxa的激活。出没DNA位点包含潜在的HoxA激活增强子，而出没RNA则起到阻止HoxA异常表达的作用。这项工作揭示了lncRNA介导的HOXA簇转录调控的多方面模型，对lncRNA转录本及其基因组位置具有不同的作用，同时说明了基于CRISPR/Cas9的快速基因组编辑在分配lncRNA功能方面的力量。
Long noncoding RNAs (lncRNAs) have been implicated in controlling various aspects of embryonic stem cell (ESC) biology, although the functions of specific lncRNAs, and the molecular mechanisms through which they act, remain unclear. Here, we demonstrate discrete and opposing roles for the lncRNA transcript Haunt and its genomic locus in regulating the HOXA gene cluster during ESC differentiation. Reducing or enhancing Haunt expression, with minimal disruption of the Haunt locus, led to upregulation or downregulation of HOXA genes, respectively. In contrast, increasingly large genomic deletions within the Haunt locus attenuated HOXA activation. The Haunt DNA locus contains potential enhancers of HOXA activation, whereas Haunt RNA acts to prevent aberrant HOXA expression. This work reveals a multifaceted model of lncRNA-mediated transcriptional regulation of the HOXA cluster, with distinct roles for a lncRNA transcript and its genomic locus, while illustrating the power of rapid CRISPR/Cas9-based genome editing for assigning lncRNA functions.