Non-homeodomain regions of Hox proteins mediate activation versus repression of Six2 via a single enhancer site in vivo

Hox genes control many developmental events along the AP axis, but few target genes have been identified. Whether target genes are activated or repressed, what enhancer elements are required for regulation, and how different domains of the Hox proteins contribute to regulatory specificity are poorly understood. Six2 is genetically downstream of both the Hox11 paralogous genes in the developing mammalian kidney and Hoxa2 in branchial arch and facial mesenchyme. Loss-of-function of Hox11 leads to loss of Six2 expression and loss-of-function of Hoxa2 leads to expanded Six2 expression. Herein we demonstrate that a single enhancer site upstream of the Six2 coding sequence is responsible for both activation by Hox11 proteins in the kidney and repression by Hoxa2 in the branchial arch and facial mesenchyme in vivo. DNA-binding activity is required for both activation and repression, but differential activity is not controlled by differences in the homeodomains. Rather, protein domains N- and C-terminal to the homeodomain confer activation versus repression activity. These data support a model in which the DNA-binding specificity of Hox proteins in vivo may be similar, consistent with accumulated in vitro data, and that unique functions result mainly from differential interactions mediated by non-homeodomain regions of Hox proteins.     

PcG蛋白复合体对Hox基因调节的研究

PcG蛋白广泛参与到生长、发育、增殖、分化以及肿瘤发生等重要过程.而目前为止对PcG蛋白的靶基因研究最透彻的就是Hox家族. Hox基因存在于一个高度保守的基因簇内,在调控维持正常发育及肿瘤发生中有重要作用.一般认为,PcG蛋白复合物对Hox基因进行以组蛋白表观修饰为主的沉默作用,指导Hox基因适时适地发挥功能. 同时,这个过程还需要DNA连接蛋白、ncRNA等分子的辅助.本文对Hox基因和PcG蛋白的组成和功能进行介绍,并重点归纳总结了对二者关系的经典和最新认识.