Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferation
Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferation
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DOI：
10.1073/pnas.0704089104
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发表时间：
2007-09-25
影响因子：
11.1
通讯作者：
Shi, Yanhong
中科院分区：
文献类型：
--
作者：
Sun, GuoQiang;Yu, Ruth T.;Shi, Yanhong
TLX是一种对神经干细胞增殖和自我更新至关重要的转录因子。然而，tlx介导的神经干细胞增殖和自我更新的分子机制在很大程度上是未知的。我们在这里表明，TLX向其下游靶基因招募组蛋白去乙酰化酶（hdac）来抑制它们的转录，从而调节神经干细胞的增殖。TLX在神经干细胞中与HDAC3和HDAC5相互作用。hdac5相互作用结构域被定位到TLX残基359-385上，其中包含一个保守的核受体-共调节剂相互作用基序IXXLL。在神经干细胞中，HDAC3和HDAC5与TLX一起被募集到TLX靶基因的启动子上。hdac的募集导致TLX靶基因、周期蛋白依赖性激酶抑制剂p21(CIP1/WAF1)（p21）和肿瘤抑制基因pten的转录抑制。抑制HDAC活性或敲低HDAC表达均可显著诱导p21和pten基因表达，显著降低神经干细胞增殖，提示与tlx相互作用的HDAC在神经干细胞增殖中发挥重要作用。此外，含有最小HDAC5相互作用结构域的TLX肽的表达破坏了TLX-HDAC5相互作用。这种相互作用的破坏导致p21和pten基因表达的显著诱导，并显著抑制神经干细胞的增殖。综上所述，这些发现证明了TLX-HDAC相互作用通过转录抑制p21和pten基因表达来促进神经干细胞增殖的机制。
TLX is a transcription factor that is essential for neural stem cell proliferation and self-renewal. However, the molecular mechanism of TLX-mediated neural stem cell proliferation and self-renewal is largely unknown. We show here that TLX recruits histone deacetylases (HDACs) to its downstream target genes to repress their transcription, which in turn regulates neural stem cell proliferation. TLX interacts with HDAC3 and HDAC5 in neural stem cells. The HDAC5-interaction domain was mapped to TLX residues 359-385, which contains a conserved nuclear receptor-coregulator interaction motif IXXLL. Both HDAC3 and HDAC5 have been shown to be recruited to the promoters of TLX target genes along with TLX in neural stem cells. Recruitment of HDACs led to transcriptional repression of TLX target genes, the cyclin-dependent kinase inhibitor, p21(CIP1/WAF1)(p21), and the tumor suppressor gene, pten. Either inhibition of HDAC activity or knockdown of HDAC expression led to marked induction of p21 and pten gene expression and dramatically reduced neural stem cell proliferation, suggesting that the TLX-interacting HDACs play an important role in neural stem cell proliferation. Moreover, expression of a TLX peptide containing the minimal HDAC5 interaction domain disrupted the TLX-HDAC5 interaction. Disruption of this interaction led to significant induction of p21 and pten gene expression and to dramatic inhibition of neural stem cell proliferation. Taken together, these findings demonstrate a mechanism for neural stem cell proliferation through transcriptional repression of p21 and pten gene expression by TLX-HDAC interactions.