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Pathways that form pericentric heterochromatin

chromosomePericentric heterochromatin is a major repressive chromatin domain in the nucleus. It is mainly composed of major and minor satellite repeats that can easily by visualized as DAPI-dense spots in interphase nuclei. Different functions have been assigned to this repressive compartment. Being a region of kinetochore attachment in mitosis, chromatin structure is thought to ensure chromosome segregation. However, pericentric heterochromatin seems to play important roles in organizing the repressive compartments of the nucleus and to ensure gene repression. This probably works by recruitment of silenced genes to the pericentric compartment as shown for imprinting or allelic exclusion during B cell development (Roldan et al., 2005). Pericentric heterochromatin is enriched for epigenetic modifications which correlate with gene repression and therefore it represents a valuable model to study mechanisms of gene silencing. A good understanding of how heterochromatin is established and maintained will ultimately enhance our understanding of stable gene repression.

 

sequential_pathwayWhat are the epigenetic modifications of pericentric heterochromatin and how are they established? The major histone lysine methylation marks at pericentric heterochromatin are H3K9me3 and H4K20me3. Suv39h1 and Suv39h2 enzymes establish H3K9me3 and, more recently, we could identify Suv4-20h1 and Suv4-20h2 as the major enzymes to induce H4K20me3. Notably, we discovered a sequential pathway that connects these two histone methylation systems (Figure 2, Schotta et al., 2004). H3K9me3 is established first, providing a binding platform for HP1 proteins. HP1 isoforms in turn recruit Suv4-20h enzymes which establish H4K20me3. Consistent with these findings, H4K20me3 is lost in either Suv39h double null (dn) or HP1 mutants. Another major epigenetic modification of pericentric heterochromatin is DNA methylation. There is evidence for a complex interplay of Suv39h enzymes (and H3K9me3) with DNA methyltransferases, however, it is currently not understood at a mechanistic level (Lehnertz et al., 2003). A number of other factors can affect the normal epigenetic profile of pericentric heterochromatin. Cells which are triply deficient for Rb family proteins show selective reduction of pericentric H4K20me3 (Gonzalo et al., 2005). Interestingly, a reduced level of H4K20me3 is a hallmark for tumor cells (Fraga et al., 2005). Thus, thorough mechanistic insight into epigenetic programming of pericentric heterochromatin will enhance our understanding of many important cellular processes ranging from cancer to aging.

 

References:

 

Fraga, M.F., Ballestar, E., Villar-Garea, A., Boix-Chornet, M., Espada, J., Schotta, G., Bonaldi, T., Haydon, C., Ropero, S., Petrie, K., Iyer, N.G., Perez-Rosado, A., Calvo, E., Lopez, J.A., Cano, A., Calasanz, M.J., Colomer, D., Piris, M.A., Ahn, N., Imhof, A., Caldas, C., Jenuwein, T., and Esteller, M. 2005. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37(4): 391-400.

Gonzalo, S., Garcia-Cao, M., Fraga, M.F., Schotta, G., Peters, A.H., Cotter, S.E., Eguia, R., Dean, D.C., Esteller, M., Jenuwein, T., and Blasco, M.A. 2005. Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nat Cell Biol 7(4): 420-428.

Lehnertz, B., Ueda, Y., Derijck, A.A., Braunschweig, U., Perez-Burgos, L., Kubicek, S., Chen, T., Li, E., Jenuwein, T., and Peters, A.H. 2003. Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr Biol 13(14): 1192-1200.

Roldan, E., Fuxa, M., Chong, W., Martinez, D., Novatchkova, M., Busslinger, M., and Skok, J.A. 2005. Locus 'decontraction' and centromeric recruitment contribute to allelic exclusion of the immunoglobulin heavy-chain gene. Nat Immunol 6: 31-41.

Schotta, G., Lachner, M., Sarma, K., Ebert, A., Sengupta, R., Reuter, G., Reinberg, D., and Jenuwein, T. 2004. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev 18(11): 1251-1262.