Identification and analysis of large intergenic non-coding RNAs regulated by p53 family members through a genome-wide analysis of p53-binding sites
Identification and analysis of large intergenic non-coding RNAs regulated by p53 family members through a genome-wide analysis of p53-binding sites
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DOI：
10.1093/hmg/ddt673
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发表时间：
2014-06-01
影响因子：
3.5
通讯作者：
Tokino, Takashi
中科院分区：
文献类型：
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作者：
Idogawa, Masashi;Ohashi, Tomoko;Tokino, Takashi
p53是已知的最重要的肿瘤抑制基因之一，并且它在大约一半的人类癌症中失活。p53家族成员通过调节转录调控来执行各种功能，例如凋亡诱导和细胞周期停滞。因此，必须探索p53家族的直接转录靶点，以阐明家族成员的功能机制。为了确定p53家族成员的直接转录靶点，我们进行了染色质免疫沉淀和下一代测序（ChIP-seq），并在整个人类基因组中搜索p53结合基序。在鉴定的ChIP-seq峰中，大约一半位于基因间区域。因此，我们假设大的基因间非编码RNA（lincRNA）是p53家族的主要靶标。最近的研究表明lincRNA在多种生物学和病理学过程中发挥重要作用，如发育、分化、干细胞和癌的发生。通过ChIP-seq和计算机分析的组合，我们发现了23种被p53家族上调的lincRNA。此外，特定lincRNA的敲除可调节p53诱导的细胞凋亡并促进基因簇的转录。我们的研究结果表明，p53家族成员和lincRNA构成了一个复杂的转录网络，参与各种生物学功能和肿瘤抑制。
p53 is one of the most important known tumor suppressor genes, and it is inactivated in approximately half of human cancers. p53 family members execute various functions, such as apoptosis induction and cell cycle arrest, by modulating transcriptional regulation. Therefore, the direct transcriptional targets of the p53 family must be explored to elucidate the functional mechanisms of family members. To identify the direct transcriptional targets of p53 family members, we performed chromatin immunoprecipitation together with next-generation sequencing (ChIP-seq) and searched for p53-binding motifs across the entire human genome. Among the identified ChIP-seq peaks, approximately half were located in an intergenic region. Therefore, we assumed large intergenic non-coding RNAs (lincRNAs) to be major targets of the p53 family. Recent reports have revealed that lincRNAs play an important role in various biological and pathological processes, such as development, differentiation, stemness and carcinogenesis. Through a combination of ChIP-seq and in silico analyses, we found 23 lincRNAs that are upregulated by the p53 family. Additionally, knockdown of specific lincRNAs modulated p53-induced apoptosis and promoted the transcription of a gene cluster. Our results suggest that p53 family members, and lincRNAs constitute a complex transcriptional network involved in various biological functions and tumor suppression.