Pitx1 broadly associates with limb enhancers and is enriched on hindlimb cis-regulatory elements.
Pitx1 broadly associates with limb enhancers and is enriched on hindlimb cis-regulatory elements.
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DOI：
10.1016/j.ydbio.2012.11.017
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发表时间：
2013-02-01
影响因子：
2.7
通讯作者：
Menke, Douglas B.
中科院分区：
文献类型：
--
作者：
Infante, Carlos R.;Park, Sungdae;Mihala, Alexandra G.;Kingsley, David M.;Menke, Douglas B.
大量的功能分析表明，垂体同源结构域转录因子Pitx1在脊椎动物后肢形态中起着关键作用。然而，关于Pitx1作用的靶基因和顺式调控元件知之甚少。早期研究表明，后肢转录因子Tbx4、HoxC10和HoxC11可能是Pitx1的转录靶点，但缺乏直接调控相互作用的明确证据。通过对小鼠胚胎后肢进行ChIP-Seq分析，我们确定了小鼠后肢发育过程中Pitx1结合位点的全基因组位置，并确定了Pitx1的潜在基因靶点。我们确定Pitx1结合在参与肢体形态发生的基因附近显著富集，包括Tbx4、HoxC10和HoxC11。值得注意的是，Pitx1与先前鉴定的Tbx4基因的HLEA和HLEB后肢增强子以及新鉴定的Tbx2后肢增强子结合。此外，与H3K27ac差异标记的前肢特异性顺式调节特征相比，Pitx1结合在后肢显著富集。然而，我们的分析显示，Pitx1也与许多功能验证的肢体增强子密切相关，这些增强子在前肢和后肢的胚胎间质中表现出相似的活性水平。我们推测Pitx1通过激活后肢特异性增强子以及通过在两组肢体中都有活性的后肢特异性增强子调节来影响后肢形态。
Extensive functional analyses have demonstrated that the pituitary homeodomain transcription factor Pitx1 plays a critical role in specifying hindlimb morphology in vertebrates. However, much less is known regarding the target genes and cis-regulatory elements through which Pitx1 acts. Earlier studies suggested that the hindlimb transcription factors Tbx4, HoxC10, and HoxC11 might be transcriptional targets of Pitx1, but definitive evidence for direct regulatory interactions has been lacking. Using ChIP-Seq on embryonic mouse hindlimbs, we have pinpointed the genome-wide location of Pitx1 binding sites during mouse hindlimb development and identified potential gene targets for Pitx1. We determined that Pitx1 binding is significantly enriched near genes involved in limb morphogenesis, including Tbx4, HoxC10, and HoxC11. Notably, Pitx1 is bound to the previously identified HLEA and HLEB hindlimb enhancers of the Tbx4 gene and to a newly identified Tbx2 hindlimb enhancer. Moreover, Pitx1 binding is significantly enriched on hindlimb relative to forelimb-specific cis-regulatory features that are differentially marked by H3K27ac. However, our analysis revealed that Pitx1 also strongly associates with many functionally verified limb enhancers that exhibit similar levels of activity in the embryonic mesenchyme of forelimbs and hindlimbs. We speculate that Pitx1 influences hindlimb morphology both through the activation of hindlimb specific enhancers as well as through the hindlimb-specific modulation of enhancers that are active in both sets of limbs.
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