Identification of novel Pax8 targets in FRTL-5 thyroid cells by gene silencing and expression microarray analysis.
Identification of novel Pax8 targets in FRTL-5 thyroid cells by gene silencing and expression microarray analysis.
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DOI：
10.1371/journal.pone.0025162
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Zannini M
中科院分区：
文献类型：
--
作者：
Di Palma T;Conti A;de Cristofaro T;Scala S;Nitsch L;Zannini M
甲状腺滤泡细胞（TFC）是迄今为止甲状腺中最丰富的细胞群，其分化程序依赖于序列特异性转录因子和转录共调节因子与细胞基础转录机制之间的相互作用。然而，导致甲状腺细胞完全分化的分子机制仍然是深入研究的对象。转录因子 Pax8 是配对盒基因家族的成员，已被证明是甲状腺滤泡细胞正常发育和分化所需的关键调节因子。尽管 Pax8 在调节涉及甲状腺分化的基因中的作用得到了充分表征，但缺乏旨在识别其他 Pax8 靶标的基因组学方法，并且该转录因子控制的生物途径在很大程度上是未知的。为了确定 Pax8 的独特下游靶标，我们研究了 Pax8 沉默的全基因组效应，比较了沉默的 FRTL-5 甲状腺细胞与正常分化的 FRTL-5 甲状腺细胞的转录组。总共有 2815 个基因在 Pax8 RNAi 后 72 小时被发现受到调节、诱导或抑制。先前报道的在 FRTL-5 细胞中受 Pax8 调节的基因得到了证实。此外，还新鉴定了参与DNA复制、阴离子转运、激酶活性、细胞凋亡和细胞过程等功能过程的新靶基因。转录组分析强调 Pax8 是甲状腺形态发生和分化的关键分子。这是第一项旨在鉴定 Pax8（甲状腺发育和分化的主要调节因子）调节的新基因的大规模研究。 Pax8 控制的生物途径和靶基因对于了解甲状腺疾病的进展以及制定新的治疗策略具有相当重要的意义。
The differentiation program of thyroid follicular cells (TFCs), by far the most abundant cell population of the thyroid gland, relies on the interplay between sequence-specific transcription factors and transcriptional coregulators with the basal transcriptional machinery of the cell. However, the molecular mechanisms leading to the fully differentiated thyrocyte are still the object of intense study. The transcription factor Pax8, a member of the Paired-box gene family, has been demonstrated to be a critical regulator required for proper development and differentiation of thyroid follicular cells. Despite being Pax8 well-characterized with respect to its role in regulating genes involved in thyroid differentiation, genomics approaches aiming at the identification of additional Pax8 targets are lacking and the biological pathways controlled by this transcription factor are largely unknown. To identify unique downstream targets of Pax8, we investigated the genome-wide effect of Pax8 silencing comparing the transcriptome of silenced versus normal differentiated FRTL-5 thyroid cells. In total, 2815 genes were found modulated 72 h after Pax8 RNAi, induced or repressed. Genes previously reported to be regulated by Pax8 in FRTL-5 cells were confirmed. In addition, novel targets genes involved in functional processes such as DNA replication, anion transport, kinase activity, apoptosis and cellular processes were newly identified. Transcriptome analysis highlighted that Pax8 is a key molecule for thyroid morphogenesis and differentiation. This is the first large-scale study aimed at the identification of new genes regulated by Pax8, a master regulator of thyroid development and differentiation. The biological pathways and target genes controlled by Pax8 will have considerable importance to understand thyroid disease progression as well as to set up novel therapeutic strategies.
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