Terranova Rémi, Agherbi Hanane, Boned Annie, Meresse Stéphane, Djabali Malek
Centre d'Immunologie de Marseille-Luminy, Institut National de la Santé et de la Recherche Médicale-Centre National de la Recherche Scientifique, Case 906, 13288 Marseille Cedex 9, France.
Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6629-34. doi: 10.1073/pnas.0507425103. Epub 2006 Apr 17.
The Mll gene is a member of the mammalian trithorax group, involved with the antagonistic Polycomb group in epigenetic regulation of homeotic genes. MLL contains a highly conserved SET domain also found in various chromatin proteins. In this study, we report that mice in which this domain was deleted by homologous recombination in ES cells (DeltaSET) exhibit skeletal defects and altered transcription of particular Hox genes during development. Chromatin immunoprecipitation and bisulfite sequencing analysis on developing embryo tissues demonstrate that this change in gene expression is associated with a dramatic reduction in histone H3 Lysine 4 monomethylation and DNA methylation defects at the same Hox loci. These results establish in vivo that the major function of Mll is to act at the chromatin level to sustain the expression of selected target Hox genes during embryonic development. These observations provide previously undescribed evidence for the in vivo relationship and SET domain dependence between histone methylation and DNA methylation on MLL target genes during embryonic development.
Mll基因是哺乳动物三胸节基因家族的成员，与同源异型基因表观遗传调控中的拮抗多梳基因家族相关。MLL含有一个在各种染色质蛋白中也存在的高度保守的SET结构域。在本研究中，我们报告通过胚胎干细胞中的同源重组删除该结构域的小鼠（DeltaSET）在发育过程中表现出骨骼缺陷和特定Hox基因转录改变。对发育中的胚胎组织进行染色质免疫沉淀和亚硫酸氢盐测序分析表明，基因表达的这种变化与同一Hox基因座处组蛋白H3赖氨酸4单甲基化的显著减少和DNA甲基化缺陷有关。这些结果在体内证实，Mll的主要功能是在染色质水平发挥作用，以维持胚胎发育过程中选定的靶标Hox基因的表达。这些观察结果为胚胎发育过程中MLL靶基因上组蛋白甲基化和DNA甲基化之间的体内关系和SET结构域依赖性提供了先前未描述的证据。
