Over-expression of the SUV39H1 histone methyltransferase induces altered proliferation and differentiation in transgenic mice

The development of multi-cellular organisms is regulated by the ordered def inition of gene expression programmes that govern cell proliferation and di fferentiation. Although differential gene activity is mainly controlled by transcription factors, it is also dependent upon the underlying chromatin s tructure, which can stabilize transcriptional 'on' or 'off' states. We have recently isolated human (SUV39H1) and mouse (Suv39h1) histone methyltransf erases (HMTases) and shown that they are important regulators for the organ ization of repressive chromatin domains. To investigate whether a SUV39H1-i nduced modulation of heterochromatin would affect mammalian development, we generated transgenic mice that over-express the SUV39H1 HMTase early durin g embryogenesis. SUV39H1 transgenic mice are growth retarded, display a wea k penetrance of skeletal transformations and are largely characterized by i mpaired erythroid differentiation, consistent with highest transgene expres sion in foetal liver. Ex vivo transgenic foetal liver cultures initially co ntain reduced numbers of cells in G1 but progress to immortalized erythrobl asts that are compromised in executing an erythroid differentiation program me. The outgrowing SUV39H1-immortalized erythroblasts can maintain a diploi d karyotype despite deregulation of several tumour suppressor proteins and dispersed distribution of the heterochromatin component HPI. Together, thes e data provide evidence for a role of the SUV39H1 HMTase during the mammali an development and indicate a possible function for higher-order chromatin in contributing to the balance between proliferation and differentiation po tentials of progenitor cells. (C) 2001 Elsevier Science Ireland Ltd. All ri ghts reserved.