Regulation of CpG island promoters by the histone methyltransferase MLL2

[摘要] MLL2 is a H3K4 specific HMT which vital for normal embryonic development in the mouse. Little is known on how MLL2 is recruited to its target genes and activates transcription. To gain insight into the molecular mechanism underlyingMLL2 function, we focused on a knownMLL2 target gene: Magoh2. This gene is controlled by a CpG island promoter and is ubiquitously expressed. Our results demonstrate that in the absence of MLL2, the Magoh2 promoter is methylated and Magoh2 is transcriptionally silenced. The Magoh2 promoter adopts the active conformationonly in the presence of MLL2.PolII is lost from theMagoh2 promoter in the absence ofMLL2, resulting in Magoh2 down-regulation. We observed loss of H3K4me\(_3\)and H3K9ac and relocation of a nucleosome over the promoter, coinciding with the onset of DNA methylation. Use of ORB and a-amanitindemonstrated that neither transcription nor the presence of Pol II are required for the maintenance of H3K4me\(_3\). Magoh2 silencingcan be overcome by re-introducing full-length MLL2. We investigated the role of MLL2 in haemopoiesis and demonstrated that MLL2 is vital for macrophage differentiationfrom embryoid bodies. MLL2 may be required for correct upregulation of Flk1 and generationof haem angioblast cells. When M//2 was deleted in haemangioblasts, the haemopoietictranscriptionalprogramwas perturbed suggestingthat MLL2 may also play a role at this later developmental stage.

[发布机构] University:University of Birmingham;Department:Institute of Biomedical Research

[关键词] Q Science;QH Natural history;QH301 Biology