Polycomb mediated epigenetic silencing and replication timing at the INK4a/ARF locus during senescence.
Polycomb mediated epigenetic silencing and replication timing at the INK4a/ARF locus during senescence.
复制标题
Polycomb 在衰老过程中介导 INK4a/ARF 位点的表观遗传沉默和复制计时。
DOI：
10.1371/journal.pone.0005622
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发表时间：
2009-05-20
期刊：
影响因子：
3.7
通讯作者：
Djabali M
中科院分区：
文献类型：
--
作者：
Agherbi H;Gaussmann-Wenger A;Verthuy C;Chasson L;Serrano M;Djabali M
INK4/ARF位点编码三个肿瘤抑制基因（p15Ink4b、ARF和p16Ink4a），在大量人类癌症中经常失活。调控INK4/ARF表达的机制尚未完全确定。本研究表明，在年轻的增殖性胚胎成纤维细胞（mef）中，Polycomb repression Complex 2 （PRC2）成员EZH2以及PRC1成员BMI1和M33在INK4/ARF调控结构域（RD）强烈表达和定位，该结构域被认为是DNA复制的起源。当细胞进入衰老时，PRC1和PRC2复合物与RD的结合丢失，导致组蛋白H3K27三甲基化水平降低（H3K27me3）。这种缺失伴随着组蛋白去甲基化酶Jmjd3的表达增加和MLL1蛋白的募集，并与Ink4a/Arf基因的表达相关。此外，我们发现Polycomb蛋白BMI1与真核细胞中DNA复制的重要调节因子CDC6相互作用。最后，我们证明了Polycomb蛋白和相关的表观遗传标记对于控制衰老过程中INK4a/ARF基因座的复制时间至关重要。我们发现复制许可因子CDC6是Polycomb组成员BMI1的新伙伴。我们的研究结果表明，在年轻细胞中，Polycomb蛋白通过CDC6被募集到INK4/ARF位点，由此产生的沉默位点在s期后期被复制。衰老后，Jmjd3过表达，MLL1蛋白被募集到位点，引发Polycomb与INK4/ARF位点的解离，在s期早期进行转录激活和复制。总之，这些结果提供了一个统一的模型，整合了INK4/ARF位点的复制、转录和表观遗传学。
The INK4/ARF locus encodes three tumor suppressor genes (p15Ink4b, Arf and p16Ink4a) and is frequently inactivated in a large number of human cancers. Mechanisms regulating INK4/ARF expression are not fully characterized. Here we show that in young proliferating embryonic fibroblasts (MEFs) the Polycomb Repressive Complex 2 (PRC2) member EZH2 together with PRC1 members BMI1 and M33 are strongly expressed and localized at the INK4/ARF regulatory domain (RD) identified as a DNA replication origin. When cells enter senescence the binding to RD of both PRC1 and PRC2 complexes is lost leading to a decreased level of histone H3K27 trimethylation (H3K27me3). This loss is accompanied with an increased expression of the histone demethylase Jmjd3 and with the recruitment of the MLL1 protein, and correlates with the expression of the Ink4a/Arf genes. Moreover, we show that the Polycomb protein BMI1 interacts with CDC6, an essential regulator of DNA replication in eukaryotic cells. Finally, we demonstrate that Polycomb proteins and associated epigenetic marks are crucial for the control of the replication timing of the INK4a/ARF locus during senescence. We identified the replication licencing factor CDC6 as a new partner of the Polycomb group member BMI1. Our results suggest that in young cells Polycomb proteins are recruited to the INK4/ARF locus through CDC6 and the resulting silent locus is replicated during late S-phase. Upon senescence, Jmjd3 is overexpressed and the MLL1 protein is recruited to the locus provoking the dissociation of Polycomb from the INK4/ARF locus, its transcriptional activation and its replication during early S-phase. Together, these results provide a unified model that integrates replication, transcription and epigenetics at the INK4/ARF locus.
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DOI：
10.1101/sqb.1994.059.01.010
发表时间：
1994-01-01
期刊：
COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY
影响因子：
--
作者：
DIMRI, GP;CAMPISI, J
通讯作者：
CAMPISI, J
DOI：
10.1073/pnas.94.9.4587
发表时间：
1997-04-29
影响因子：
11.1
作者：
Hansen, RS;Canfield, TK;Gartler, SM
通讯作者：
Gartler, SM
影响因子：
64.8
作者：
Katoh-Fukui, Y;Tsuchiya, R;Higashinakagawa, T
通讯作者：
Higashinakagawa, T
影响因子：
64.5
作者：
Czermin, B;Melfi, R;Pirrotta, V
通讯作者：
Pirrotta, V
影响因子：
1.6
作者：
Gonzalez, A. Gonzalez;Naldi, A.;Chaouiya, C.
通讯作者：
Chaouiya, C.