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The role of lysine methyltransferase Ehmt2/G9a in mesenchymal development

University of British Columbia

The euchromatic histone methyltransferase 2 (Ehmt2), aka. G9a, is responsible for methylating histone H3 at lysine 9. However, it is a multifaceted gene whose functions sometimes exceed histone-tail modifications, and the nature and importance of its regulatory effects differ vastly between different tissue systems. A number of lines of evidence hint at its critical role in the developmental biology and tissue biology of mesenchymal tissues. In this work I assessed the role of Ehmt2 in skeletal muscle, adipose tissues, and craniofacial development. Previous publications employing immortalised cell lines have proposed that Ehmt2 is an important inhibitor of myogenic differentiation. In addition to the well-known repressive effects of H3K9 dimethylation, for which Ehmt2 is largely responsible, it was postulated that it can directly methylate MYOD, a master regulator of myogenesis, and lead to repression of myogenic cell differentiation. In a mouse model to validate this, I found conditional knockout muscle stem cells activated, proliferated, and differentiated normally without Ehmt2. Knockout mice under the control of Myod-Cre developed and regenerated normally after acute injury to leg muscle, refuting the previous theory that Ehmt2 is required for myogenesis. The global loss of H3K9 dimethylation in normal myogenesis also signalled that this histone tail modification is largely irrelevant in skeletal muscle. Despite the gene’s dispensability in a number of developmental tissues, Ehmt2-/- mice die early during embryogenesis. In order to uncover the role of Ehmt2 in other mesenchymal tissues, I generated a transgenic mouse line to conditionally delete Ehmt2 during mesoderm and neural crest development. I found that the loss of Ehmt2 in the Pdgfra developmental lineage resulted in striking yet highly reproducible craniofacial malformations. Adipose tissue is also an important topic in the understanding of Ehmt2, especially since previous publications have found its importance in white adipose tissue, and its homologue, Ehmt1/GLP, to be required for brown adipose tissue specification and activation. The PdgfraCre Ehmt2floxed/null mouse model revealed novel in vivo insight for the role in which Ehmt2 limits lipid accumulation and is required for normal brown adipose development.

Text

2017-01-21

Attribution-NonCommercial-ShareAlike 4.0 International

http://hdl.handle.net/2429/60355

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-sa/4.0/