Massive reshaping of genome-nuclear lamina interactions during oncogene-induced senescence.
Massive reshaping of genome-nuclear lamina interactions during oncogene-induced senescence.
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DOI：
10.1101/gr.225763.117
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发表时间：
2017-10
期刊：
影响因子：
7
通讯作者：
Peeper DS
中科院分区：
文献类型：
--
作者：
Lenain C;de Graaf CA;Pagie L;Visser NL;de Haas M;de Vries SS;Peric-Hupkes D;van Steensel B;Peeper DS
细胞衰老是一种几乎不可逆地抑制细胞响应各种应激信号的增殖能力的机制。这包括激活癌基因的表达，从而导致癌基因诱导衰老（OIS）。大量证据表明 OIS 涉及染色质重组，包括衰老相关异染色质灶 (SAHF) 的形成。核层（NL）是基因组组织的重要贡献者，与细胞衰老和生物体衰老有关。它与基因组的多个区域（称为层相关域（LAD））相互作用。一些 LAD 是细胞类型特异性的，而其他 LAD 在细胞类型之间是保守的，被称为组成型 LAD (cLAD)。在这里，我们使用 DamID 来研究由常见 BRAFV600E 癌基因的表达触发的 OIS 模型中基因组与 NL 相互作用的变化。我们发现 OIS 细胞丢失了大部分 cLADS，这表明丢失了将 cLAD 靶向 NL 的特定机制。此外，多个基因重新定位到NL。出乎意料的是，他们没有受到镇压，这意味着国家联盟在 OIS 期间的镇压活动被废除。最后，OIS 细胞表现出端粒与 NL 的关联性增强。我们的研究揭示了衰老细胞获得了一种新型的 LAD 组织，并表明存在将 cLAD 与 NL 结合并抑制 NL 基因表达的未知机制。
Cellular senescence is a mechanism that virtually irreversibly suppresses the proliferative capacity of cells in response to various stress signals. This includes the expression of activated oncogenes, which causes Oncogene-Induced Senescence (OIS). A body of evidence points to the involvement in OIS of chromatin reorganization, including the formation of senescence-associated heterochromatic foci (SAHF). The nuclear lamina (NL) is an important contributor to genome organization and has been implicated in cellular senescence and organismal aging. It interacts with multiple regions of the genome called lamina-associated domains (LADs). Some LADs are cell-type specific, whereas others are conserved between cell types and are referred to as constitutive LADs (cLADs). Here, we used DamID to investigate the changes in genome–NL interactions in a model of OIS triggered by the expression of the common BRAFV600E oncogene. We found that OIS cells lose most of their cLADS, suggesting the loss of a specific mechanism that targets cLADs to the NL. In addition, multiple genes relocated to the NL. Unexpectedly, they were not repressed, implying the abrogation of the repressive activity of the NL during OIS. Finally, OIS cells displayed an increased association of telomeres with the NL. Our study reveals that senescent cells acquire a new type of LAD organization and suggests the existence of as yet unknown mechanisms that tether cLADs to the NL and repress gene expression at the NL.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
16
作者：
Chandra, Tamir;Kirschner, Kristina;Thuret, Jean-Yves;Pope, Benjamin D.;Ryba, Tyrone;Newman, Scott;Ahmed, Kashif;Samarajiwa, Shamith A.;Salama, Rafik;Carroll, Thomas;Stark, Rory;Janky, Rekin's;Narita, Masako;Xue, Lixiang;Chicas, Agustin;Nunez, Sabrina;Janknecht, Ralf;Hayashi-Takanaka, Yoko;Wilson, Michael D.;Marshall, Aileen;Odom, Duncan T.;Babu, M. Madan;Bazett-Jones, David P.;Tavare, Simon;Edwards, Paul A. W.;Lowe, Scott W.;Kimura, Hiroshi;Gilbert, David M.;Narita, Masashi
通讯作者：
Narita, Masashi
影响因子：
64.5
作者：
Kind J;Pagie L;de Vries SS;Nahidiazar L;Dey SS;Bienko M;Zhan Y;Lajoie B;de Graaf CA;Amendola M;Fudenberg G;Imakaev M;Mirny LA;Jalink K;Dekker J;van Oudenaarden A;van Steensel B
通讯作者：
van Steensel B
影响因子：
11.4
作者：
Gonzalez-Suarez, Ignacio;Redwood, Abena B.;Gonzalo, Susana
通讯作者：
Gonzalo, Susana
影响因子：
64.8
作者：
Guelen, Lars;Pagie, Ludo;van Steensel, Bas
通讯作者：
van Steensel, Bas