ATRX Plays a Key Role in Maintaining Silencing at Interstitial Heterochromatic Loci and Imprinted Genes.
ATRX Plays a Key Role in Maintaining Silencing at Interstitial Heterochromatic Loci and Imprinted Genes.
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DOI：
10.1016/j.celrep.2015.03.036
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发表时间：
2015-04-21
期刊：
影响因子：
8.8
通讯作者：
Gibbons RJ
中科院分区：
文献类型：
--
作者：
Voon HP;Hughes JR;Rode C;De La Rosa-Velázquez IA;Jenuwein T;Feil R;Higgs DR;Gibbons RJ
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翻转的组蛋白。H3.3沉积在常染色质上依赖于HIRA，而ATRX/Daxx将H3.3沉积在臂间异染色质和端粒上。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的异常端粒延长有关。在这项研究中，我们表明，ATRX依赖的沉积H3.3不限于臂间异染色质和端粒，但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ESC中沉默的印迹等位基因。ATRX KO细胞不能在这些位点存款H3.3，导致H3 K9 me 3异染色质修饰的丧失、阻遏的丧失和异常等位基因表达。我们提出了一个模型，其中ATRX依赖性沉积H3.3到异染色质通常需要保持记忆的印记位点的沉默。ATRX将H3.3沉积在整个基因组的异染色质上ATRX和H3.3优先结合印迹DMR的甲基化等位基因H3.3沉积在印迹DMR上依赖于ATRX ATRX/H3.3的损失导致印迹DMR上H3 K9 me 3修饰的损失Voon et al.证明ATRX在印迹差异甲基化区域的甲基化等位基因处沉积组蛋白变体H3.3。ATRX敲除导致这些区域的H3.3和H3 K9 me 3异染色质修饰的丢失，表明H3.3在维持异染色质沉默中的独特作用。
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. ATRX deposits H3.3 at heterochromatin throughout the genome ATRX and H3.3 preferentially bind the methylated allele of imprinted DMRs H3.3 deposition at imprinted DMRs is dependent on ATRX Loss of ATRX/H3.3 leads to loss of H3K9me3 modification at imprinted DMRs Voon et al. demonstrate that ATRX deposits the histone variant H3.3 at the methylated allele of imprinted differentially methylated regions. ATRX knockout leads to the loss of H3.3 and the H3K9me3 heterochromatin modification at these regions, suggesting a unique role for H3.3 in maintaining heterochromatin silencing.
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影响因子：
10.5
作者：
Drane, Pascal;Ouararhni, Khalid;Hamiche, Ali
通讯作者：
Hamiche, Ali
影响因子：
64.5
作者：
Banaszynski LA;Wen D;Dewell S;Whitcomb SJ;Lin M;Diaz N;Elsässer SJ;Chapgier A;Goldberg AD;Canaani E;Rafii S;Zheng D;Allis CD
通讯作者：
Allis CD
影响因子：
16.8
作者：
Iwase, Shigeki;Xiang, Bin;Ghosh, Sharmistha;Ren, Ting;Lewis, Peter W.;Cochrane, Jesse C.;Allis, C. David;Picketts, David J.;Patel, Dinshaw J.;Li, Haitao;Shi, Yang
通讯作者：
Shi, Yang
影响因子：
--
作者：
Langmead, Ben
通讯作者：
Langmead, Ben
影响因子：
64.5
作者：
Goldberg AD;Banaszynski LA;Noh KM;Lewis PW;Elsaesser SJ;Stadler S;Dewell S;Law M;Guo X;Li X;Wen D;Chapgier A;DeKelver RC;Miller JC;Lee YL;Boydston EA;Holmes MC;Gregory PD;Greally JM;Rafii S;Yang C;Scambler PJ;Garrick D;Gibbons RJ;Higgs DR;Cristea IM;Urnov FD;Zheng D;Allis CD
通讯作者：
Allis CD