Change - SAHF

Created on Nov. 21, 2012, 5:14 p.m. by Hevok & updated on Nov. 21, 2012, 10:42 p.m. by Hevok

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 fem
lale 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siRNA o HP1b mRNA can trigger cell division in senescent human diploid fibroblasts in vitro [J.P. Brown and P.P. Singh, unpublished
]. ¶

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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. ¶

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