Institute of Experimental Endocrinology and Oncology G. Salvatore (IEOS), National Research Council, Naples, Italy.
PLoS One. 2011;6(9):e25162. doi: 10.1371/journal.pone.0025162. Epub 2011 Sep 23.
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.
METHODOLOGY/PRINCIPAL FINDINGS: 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.
CONCLUSIONS/SIGNIFICANCE: 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.
甲状腺滤泡细胞（TFC）的分化程序是甲状腺中最丰富的细胞群体，依赖于序列特异性转录因子与细胞基本转录机制之间的相互作用以及转录共调节剂。然而，导致完全分化的甲状腺细胞的分子机制仍然是研究的热点。转录因子 Pax8 是 Paired-box 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必需的关键调节因子。尽管 Pax8 在调节甲状腺分化相关基因方面的作用已得到很好的描述，但缺乏针对鉴定其他 Pax8 靶标的基因组学方法，并且该转录因子控制的生物学途径在很大程度上是未知的。
方法/主要发现：为了鉴定 Pax8 的独特下游靶标，我们比较了沉默 Pax8 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，研究了 Pax8 沉默对全基因组的影响。总共发现 2815 个基因在 Pax8 RNAi 后 72 小时被调节，被诱导或被抑制。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，还新鉴定了一些参与功能过程的新靶基因，如 DNA 复制、阴离子转运、激酶活性、细胞凋亡和细胞过程。转录组分析强调 Pax8 是甲状腺形态发生和分化的关键分子。
结论/意义：这是首次大规模研究旨在鉴定新的受 Pax8 调节的基因，Pax8 是甲状腺发育和分化的主要调节因子。Pax8 控制的生物学途径和靶基因对于理解甲状腺疾病的进展以及制定新的治疗策略具有重要意义。
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