Epigenomic signatures associated with spontaneous and replication stress-induced DNA double strand breaks.
Epigenomic signatures associated with spontaneous and replication stress-induced DNA double strand breaks.
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DOI：
10.3389/fgene.2022.907547
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发表时间：
2022
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
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作者：
共同脆弱位点（cfs）是所有个体基因组中易于发生DNA双链断裂（DSBs）并经历随后重排的特定区域。体外可通过DNA聚合酶抑制或核苷酸池干扰等轻度DNA复制胁迫诱导CFS的形成。CFS的形成机制与DNA复制时间控制、转录活性以及染色质组织有关。然而，目前尚不清楚是什么特定的顺式或反式因子调节了决定CFS形成的复制和转录之间的相互作用。我们最近首次报道了人类淋巴母细胞样细胞在阿霉素诱导的复制胁迫下DNA DSBs的全基因组定位。在这里，我们系统地比较了这些dsb与从已发表的研究中绘制的同一细胞系的邻近表观基因组特征。我们证明了阿菲霉素诱导的dsb与组蛋白3赖氨酸36三甲基化密切相关，这是一种活性转录的标记。我们进一步证明，这种DSB特征是由阿菲迪克林及其溶剂二甲基亚砜双重处理的复合效应，后者本身就能诱导转录。我们还提出了补充证据，证明dsb和3D染色体结构域与高密度基因簇和活性转录之间存在关联。此外，我们发现，虽然在14个精细定位的CFS中，除了一个外，其他所有CFS中都检测到dsb，但它们并不富集在CFS核心序列中，而是划定了CFS核心区域。与此相关的是，大于300 kb的大基因的DSB密度并不高，这与报道的这些大基因的CFS位点富集相反。最后，复制时间分析表明，CFS核心区包含起始事件，这表明在相对较高的复制应激水平下，复制动力学的改变是CFS形成的原因。
Common fragile sites (CFSs) are specific regions of all individuals’ genome that are predisposed to DNA double strand breaks (DSBs) and undergo subsequent rearrangements. CFS formation can be induced in vitro by mild level of DNA replication stress, such as DNA polymerase inhibition or nucleotide pool disturbance. The mechanisms of CFS formation have been linked to DNA replication timing control, transcription activities, as well as chromatin organization. However, it is unclear what specific cis- or trans-factors regulate the interplay between replication and transcription that determine CFS formation. We recently reported genome-wide mapping of DNA DSBs under replication stress induced by aphidicolin in human lymphoblastoids for the first time. Here, we systematically compared these DSBs with regards to nearby epigenomic features mapped in the same cell line from published studies. We demonstrate that aphidicolin-induced DSBs are strongly correlated with histone 3 lysine 36 trimethylation, a marker for active transcription. We further demonstrate that this DSB signature is a composite effect by the dual treatment of aphidicolin and its solvent, dimethylsulfoxide, the latter of which potently induces transcription on its own. We also present complementing evidence for the association between DSBs and 3D chromosome architectural domains with high density gene cluster and active transcription. Additionally, we show that while DSBs were detected at all but one of the fourteen finely mapped CFSs, they were not enriched in the CFS core sequences and rather demarcated the CFS core region. Related to this point, DSB density was not higher in large genes of greater than 300 kb, contrary to reported enrichment of CFS sites at these large genes. Finally, replication timing analyses demonstrate that the CFS core region contain initiation events, suggesting that altered replication dynamics are responsible for CFS formation in relatively higher level of replication stress.
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影响因子：
64.5
作者：
Barlow JH;Faryabi RB;Callén E;Wong N;Malhowski A;Chen HT;Gutierrez-Cruz G;Sun HW;McKinnon P;Wright G;Casellas R;Robbiani DF;Staudt L;Fernandez-Capetillo O;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
48
作者：
Crosetto, Nicola;Mitra, Abhishek;Silva, Maria Joao;Bienko, Magda;Dojer, Norbert;Wang, Qi;Karaca, Elif;Chiarle, Roberto;Skrzypczak, Magdalena;Ginalski, Krzysztof;Pasero, Philippe;Rowicka, Maga;Dikic, Ivan
通讯作者：
Dikic, Ivan
影响因子：
16.6
作者：
Brison, Olivier;El-Hilali, Sami;Chen, Chun-Long
通讯作者：
Chen, Chun-Long
影响因子：
3.8
作者：
Alt, Frederick W.;Schwer, Bjoern
通讯作者：
Schwer, Bjoern
影响因子：
12.3
作者：
Mourad R;Ginalski K;Legube G;Cuvier O
通讯作者：
Cuvier O