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

Abstract

The development of multi-cellular organisms is regulated by the ordered definition of gene expression programmes that govern cell proliferation and differentiation. Although differential gene activity is mainly controlled by transcription factors, it is also dependent upon the underlying chromatin structure, which can stabilize transcriptional "on" or "off" states. We have recently isolated human (SUV39H1) and mouse (Suv39h1) histone methyltransferases (HMTases) and shown that they are important regulators for the organization of repressive chromatin domains. To investigate whether a SUV39H1-induced modulation of heterochromatin would affect mammalian development, we generated transgenic mice that over-express the SUV39H1 HMTase early during embryogenesis. SUV39H1 transgenic mice are growth retarded, display a weak penetrance of skeletal transformations and are largely characterized by impaired erythroid differentiation, consistent with highest transgene expression in foetal liver. Ex vivo transgenic foetal liver cultures initially contain reduced numbers of cells in G1 but progress to immortalized erythroblasts that are compromised in executing an erythroid differentiation programme. The outgrowing SUV39H1-immortalized erythroblasts can maintain a diploid karyotype despite deregulation of several tumour suppressor proteins and dispersed distribution of the heterochromatin component HP1. Together, these data provide evidence for a role of the SUV39H1 HMTase during the mammalian development and indicate a possible function for higher-order chromatin in contributing to the balance between proliferation and differentiation potentials of progenitor cells.

Pocket Protein Complexes Are Recruited to Distinct Targets in Quiescent and Proliferating Cells

“…These data provide the first evidence for novel regulation of p107-selective targets in both human and mouse cells. Of particular interest is SUV39H1, a histone methyltransferase whose activity is required for heterochromatin formation and whose overexpression leads to growth retardation (11). Taken together with our observation that heterochromatin protein HP1 is also a target of pocket protein-E2F4 repression (5), our data indicate that expression of the SUV39H1-HP1 module may be entrained to the cell cycle via pocket protein-mediated regulation.…”

Epigenetic histone H3 lysine 9 methylation in metabolic memory and inflammatory phenotype of vascular smooth muscle cells in diabetes

“…However, recent reports indicate that SUV39H1-mediated H3K9me3 also occurs at euchromatic gene promoters involved in muscle differentiation and cell cycle regulation (22)(23)(24). Suv39h1 has wide ranging expression patterns in mouse tissues (25). However, the expression pattern of Suv39h1 specifically in db/db mice has not yet been explored.…”

Methylation of SUV39H1 by SET7/9 results in heterochromatin relaxation and genome instability

“…Based on this property, SUV39H1 is thought to be essential for heterochromatin stability and integrity (14,15). Evidence from transgenic mice reveals that the loss or overexpression of suv39h causes severe defects in growth and development and even genome instability and increased susceptibility to tumors (14,16). Therefore, the regulation of SUV39H1 expression or activity is critical for the maintenance of heterochromatin stability.…”