Species-Specific Strategies Underlying Conserved Functions of Metabolic Transcription Factors
Species-Specific Strategies Underlying Conserved Functions of Metabolic Transcription Factors
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DOI：
10.1210/me.2010-0454
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发表时间：
2011-04-01
影响因子：
--
通讯作者：
Kaestner, Klaus H.
中科院分区：
文献类型：
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作者：
Soccio, Raymond E.;Tuteja, Geetu;Kaestner, Klaus H.
螺旋翼蛋白FOXA2和核受体过氧化物酶体增殖激活受体γ (PPAR γ)是高度保守的区域表达转录因子（TFs），调节控制复杂代谢功能的基因网络。对小鼠肝脏中的Foxa2和小鼠脂肪细胞中的PPAR γ的citstrome分析之前已经产生了共识的结合位点，这些结合位点几乎与人类细胞中相应的tf使用的位点相同。我们在这里报道，尽管规范结合基序是保守的，但人类肝脏和ppar γ非人脂肪细胞中FOXA2的绝大多数结合区都不在小鼠基因组对应的同源位置，反之亦然。值得注意的是，尽管序列守恒，但在一个物种中可能没有TF结合，包括在其他物种中支持结合的基序，这表明了硅结合位点预测的主要局限性。虽然只有大约10%的结合位点是保守的，但基因中心分析显示，肝脏FOXA2和脂肪细胞PPAR γ约50%的TF占用基因是跨物种共享的。值得注意的是，对于这两种tf，许多共享基因在组织特异性代谢途径中起作用，而物种独特的基因在这些途径中没有表现出富集。尽管如此，物种独特的基因，像共享基因一样，在功能丧失实验中显示了预期的tf转录调节。因此，物种特异性策略是代谢tf生物学功能的基础，在哺乳动物物种中高度保守。多物种因子结合分析可能是区分明显的物种特有噪声和揭示功能相关信息的必要条件。（分子内分泌学25:694-706,2011）
The winged helix protein FOXA2 and the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma) are highly conserved, regionally expressed transcription factors (TFs) that regulate networks of genes controlling complex metabolic functions. Cistrome analysis for Foxa2 in mouse liver and PPAR gamma in mouse adipocytes has previously produced consensus-binding sites that are nearly identical to those used by the corresponding TFs in human cells. We report here that, despite the conservation of the canonical binding motif, the great majority of binding regions for FOXA2 in human liver and forPPAR gamma inhumanadipocytes are not in the orthologous locations corresponding to the mouse genome, and vice versa. Of note, TF binding can be absent in one species despite sequence conservation, including motifs that do support binding in the other species, demonstrating a major limitation of in silico binding site prediction. Whereas only approximately 10% of binding sites are conserved, gene-centric analysis reveals that about 50% of genes with nearby TF occupancy are shared across species for both hepatic FOXA2 and adipocyte PPAR gamma. Remarkably, for both TFs, many of the shared genes function in tissue-specific metabolic pathways, whereas species-unique genes fail to show enrichment for these pathways. Nonetheless, the species-unique genes, like the shared genes, showed the expected transcriptional regulation by the TFs in loss-of-function experiments. Thus, species-specific strategies underlie the biological functions of metabolic TFs that are highly conserved across mammalian species. Analysis of factor binding in multiple species may be necessary to distinguish apparent species-unique noise and reveal functionally relevant information. (Molecular Endocrinology 25: 694-706, 2011)