Pitx1 broadly associates with limb enhancers and is enriched on hindlimb cis-regulatory elements

被引:47
作者
Infante, Carlos R. [1 ]
Park, Sungdae [1 ]
Mihala, Alexandra G. [1 ]
Kingsley, David M. [2 ,3 ]
Menke, Douglas B. [1 ]
机构
[1] Univ Georgia, Dept Genet, Athens, GA 30602 USA
[2] Univ Sch Med, Dept Dev Biol, Stanford, CA 94305 USA
[3] Univ Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
Pitx1; Tbx4; Tbx2; Enhancer; Limb; ChIP-Seq; Mouse; GENE; DNA; EXPRESSION; DATABASE; BINDING; MOUSE; TBX4; TRANSCRIPTION; EFFICIENT; GENOME;
D O I
10.1016/j.ydbio.2012.11.017
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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. (C) 2012 Elsevier Inc. All rights reserved.
引用
收藏
页码:234 / 244
页数:11
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