Functional targets of the monogenic diabetes transcription factors HNF-1alpha and HNF-4alpha are highly conserved between mice and humans.
Functional targets of the monogenic diabetes transcription factors HNF-1alpha and HNF-4alpha are highly conserved between mice and humans.
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作者：
Boj SF;Servitja JM;Martin D;Rios M;Talianidis I;Guigo R;Ferrer J
转录机制的进化保守性已被广泛用于理解人类生物学和疾病。然而，近期的研究结果出乎意料地表明，转录调节因子肝细胞核因子（HNF）-1α和 -4α在小鼠和人类中很少结合到相同的基因上，这导致有人提出组织特异性转录调控在这两个物种中已经发生了广泛的分化。这些观察结果对使用小鼠模型来理解HNF - 1α和HNF - 4α缺陷型糖尿病具有重要意义。然而，在不考虑调控功能的情况下评估结合的研究的重要性却鲜为人知。
我们将先前报道的小鼠和人类HNF - 1α和HNF - 4α结合研究与独立的结合实验进行了比较。我们还将结合研究与小鼠和人类功能缺失基因表达数据集进行了整合。
首先，我们证实了物种特异性HNF - 1α和 -4α结合的存在，但也观察到在不同数据集中结合的检测不完全，导致对结合保守性的低估。其次，在没有这些调节因子的情况下，只有一小部分HNF - 1α和HNF - 4α结合的基因表达下调。这一子集的功能靶点没有显示出结合或结合序列基序进化分化的证据。最后，我们观察到保守的和物种特异性的结合特性之间存在差异。例如，保守结合更频繁地位于转录起始位点附近，并且更有可能涉及同一基因中的多个结合事件。
尽管结合存在进化变化，但HNF - 1α和 -4α的基本直接转录功能在小鼠和人类之间大体上是保守的。
The evolutionary conservation of transcriptional mechanisms has been widely exploited to understand human biology and disease. Recent findings, however, unexpectedly showed that the transcriptional regulators hepatocyte nuclear factor (HNF)-1α and -4α rarely bind to the same genes in mice and humans, leading to the proposal that tissue-specific transcriptional regulation has undergone extensive divergence in the two species. Such observations have major implications for the use of mouse models to understand HNF-1α– and HNF-4α–deficient diabetes. However, the significance of studies that assess binding without considering regulatory function is poorly understood. We compared previously reported mouse and human HNF-1α and HNF-4α binding studies with independent binding experiments. We also integrated binding studies with mouse and human loss-of-function gene expression datasets. First, we confirmed the existence of species-specific HNF-1α and -4α binding, yet observed incomplete detection of binding in the different datasets, causing an underestimation of binding conservation. Second, only a minor fraction of HNF-1α– and HNF-4α–bound genes were downregulated in the absence of these regulators. This subset of functional targets did not show evidence for evolutionary divergence of binding or binding sequence motifs. Finally, we observed differences between conserved and species-specific binding properties. For example, conserved binding was more frequently located near transcriptional start sites and was more likely to involve multiple binding events in the same gene. Despite evolutionary changes in binding, essential direct transcriptional functions of HNF-1α and -4α are largely conserved between mice and humans.
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