Amin Shilu, Donaldson Ian J, Zannino Denise A, Hensman James, Rattray Magnus, Losa Marta, Spitz François, Ladam Franck, Sagerström Charles, Bobola Nicoletta
School of Dentistry, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PT, UK.
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
Dev Cell. 2015 Feb 9;32(3):265-77. doi: 10.1016/j.devcel.2014.12.024. Epub 2015 Jan 29.
Hox transcription factors (TFs) are essential for vertebrate development, but how these evolutionary conserved proteins function in vivo remains unclear. Because Hox proteins have notoriously low binding specificity, they are believed to bind with cofactors, mainly homeodomain TFs Pbx and Meis, to select their specific targets. We mapped binding of Meis, Pbx, and Hoxa2 in the branchial arches, a series of segments in the developing vertebrate head. Meis occupancy is largely similar in Hox-positive and -negative arches. Hoxa2, which specifies second arch (IIBA) identity, recognizes a subset of Meis prebound sites that contain Hox motifs. Importantly, at these sites Meis binding is strongly increased. This enhanced Meis binding coincides with active enhancers, which are linked to genes highly expressed in the IIBA and regulated by Hoxa2. These findings show that Hoxa2 operates as a tissue-specific cofactor, enhancing Meis binding to specific sites that provide the IIBA with its anatomical identity.
Hox转录因子（TFs）对脊椎动物的发育至关重要，但这些进化上保守的蛋白质在体内如何发挥作用仍不清楚。由于Hox蛋白的结合特异性极低，人们认为它们与辅因子（主要是同源结构域TFs Pbx和Meis）结合，以选择其特定靶点。我们绘制了Meis、Pbx和Hoxa2在鳃弓中的结合图谱，鳃弓是发育中的脊椎动物头部的一系列节段。在Hox阳性和阴性弓中，Meis的占据情况大致相似。指定第二弓（IIBA）身份的Hoxa2识别包含Hox基序的Meis预结合位点的一个子集。重要的是，在这些位点，Meis的结合显著增加。这种增强的Meis结合与活跃的增强子一致，这些增强子与在IIBA中高度表达并受Hoxa2调控的基因相关联。这些发现表明，Hoxa2作为一种组织特异性辅因子发挥作用，增强Meis与特定位点的结合，这些位点赋予IIBA其解剖学身份。
