Cellular senescence is associated with dramatic nuclear reorganization and formation of the senescence-associated heterochromatin foci (SAHF) [Narita et al. 2003]. Characteristic for SAHF is H3K9me3 and heterochromatin protein 1 (HP1) as well as the variant histone macro H2A (mH2A) [Narita et al. 2003; Zhang et al. 2005]. SAHF sequesters proliferation-promoting genes (E2F-responsive genes) and thereby triggers the senescent state [Narita et al. 2003; Zhang et al. 2005].
There is a significant, quantitative, passage-associated increase in the two heterochromatin markers, HP1β and mH2A, in the nuclei of cells approaching senescence in vitro and for mH2A there is a tight correlation with aging of cells in vivo [Kreiling et al. 2011].
HP1β and mH2A epigentically regulate gene expression [Billur et al. 2010; Muthurajan et al. 2011]. HP1β binds the H3K9me3 and is involved in telomere physiology, assembly at DNA repair foci and the regulation of the pluripotence factor Oct4
mH2A is involved in epigenetic facultative heterochromatinization of inactive X-chromosome in female cells [Chow & Brown, 2003]. HP1β and mH2A co-purify with the same chromatin fragments [Changolkar & Pehrson 2006] and both co-localize in SAHF [Narita et al. 2003; Zhang et al. 2005].
Knockdown of via siRNA o HP1b mRNA can trigger cell division in senescent human diploid fibroblasts in vitro [J.P. Brown and P.P. Singh, unpublished].
Narita, M., Nunez, S., Heard, E., Lin, A.W., Hearn, S.A., Spector, D.L., Hannon, G.J. & Lowe, S.W. (2003) Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703–716.
Zhang, R., Poustovoitov, M.V., Ye, X., Santos, H.A., Chen, W., Daganzo, S.M., Erzberger, J.P., Serebriiskii, I.G., Canutescu, A.A., Dunbrack, R.L., Pehrson, J.R., Berger, J.M., Kaufman, P.D. & Adams, P.D. (2005) Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev. Cell 8, 19–30.
Kreiling, J.A., Tamamori-Adachi, M., Sexton, A.N., Jeyapalan, J.C., Munoz-Najar, U., Peterson, A.L., Manivannan, J., Rog- ers, E.S., Pchelintsev, N.A., Adams, P.D. & Sedivy, J.M. (2011) Age-associated increase in heterochromatic marks in murine and primate tissues. Aging Cell 10, 292–304
Billur, M., Bartunik, H.D. & Singh, P.B. (2010) The essential function of HP1 beta: a case of the tail wagging the dog? Trends Biochem. Sci. 35, 115–123.
Muthurajan, U.M., McBryant, S.J., Lu, X., Hansen, J.C. & Luger, K. (2011) The Linker Region of MacroH2A Promotes Self-association of Nucleosomal Arrays. J. Biol. Chem. 286, 23852–23864.
Changolkar, L.N. & Pehrson, J.R. (2006) macroH2A1 histone variants are depleted on active genes but concentrated on the inactive X chromosome. Mol. Cell. Biol. 26, 4410–4420.
Chow, J.C. & Brown, C.J. (2003) Forming facultative heterochromatin: silencing of an X chromosome in mammalian females. Cell. Mol. Life Sci. 60, 2586–2603.