Voon Hsiao P J, Hughes Jim R, Rode Christina, De La Rosa-Velázquez Inti A, Jenuwein Thomas, Feil Robert, Higgs Douglas R, Gibbons Richard J
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
Cell Rep. 2015 Apr 21;11(3):405-18. doi: 10.1016/j.celrep.2015.03.036. Epub 2015 Apr 9.
Histone H3.3 is a replication-independent histone variant, which replaces histones that are turned over throughout the entire cell cycle. H3.3 deposition at euchromatin is dependent on HIRA, whereas ATRX/Daxx deposits H3.3 at pericentric heterochromatin and telomeres. The role of H3.3 at heterochromatic regions is unknown, but mutations in the ATRX/Daxx/H3.3 pathway are linked to aberrant telomere lengthening in certain cancers. In this study, we show that ATRX-dependent deposition of H3.3 is not limited to pericentric heterochromatin and telomeres but also occurs at heterochromatic sites throughout the genome. Notably, ATRX/H3.3 specifically localizes to silenced imprinted alleles in mouse ESCs. ATRX KO cells failed to deposit H3.3 at these sites, leading to loss of the H3K9me3 heterochromatin modification, loss of repression, and aberrant allelic expression. We propose a model whereby ATRX-dependent deposition of H3.3 into heterochromatin is normally required to maintain the memory of silencing at imprinted loci.
组蛋白H3.3是一种不依赖复制的组蛋白变体，它取代了在整个细胞周期中被更替的组蛋白。H3.3在常染色质上的沉积依赖于HIRA，而ATRX/Daxx则在着丝粒周围异染色质和端粒处沉积H3.3。H3.3在异染色质区域的作用尚不清楚，但ATRX/Daxx/H3.3途径中的突变与某些癌症中端粒的异常延长有关。在本研究中，我们表明ATRX依赖的H3.3沉积不仅限于着丝粒周围异染色质和端粒，也发生在整个基因组的异染色质位点。值得注意的是，ATRX/H3.3特异性定位于小鼠胚胎干细胞中沉默的印记等位基因。ATRX基因敲除细胞未能在这些位点沉积H3.3，导致H3K9me3异染色质修饰缺失、抑制作用丧失和等位基因异常表达。我们提出了一个模型，即通常需要ATRX依赖的H3.3沉积到异染色质中，以维持印记位点沉默的记忆。
