A natural variation-based screen in mouse cells reveals USF2 as a regulator of the DNA damage response and cellular senescence.
A natural variation-based screen in mouse cells reveals USF2 as a regulator of the DNA damage response and cellular senescence.
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DOI：
10.1093/g3journal/jkad091
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发表时间：
2023-07-05
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影响因子：
--
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中科院分区：
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细胞衰老是由应激诱导的细胞周期阻滞、凋亡抵抗和细胞因子释放的过程。在实验室小鼠中进行的里程碑式研究已经表征了许多主要衰老调节因子，包括p16 INK 4a、p21、NF-κB、p53和C/EBPβ。为了发现衰老中的其他分子参与者，我们开发了一种筛选方法来利用小鼠物种之间的进化差异。我们发现，当用DNA损伤诱导衰老时，来自地中海小鼠的原代细胞产生的细胞因子和活性溶酶体比来自实验室小鼠的细胞少。我们使用等位基因特异性表达谱来编目物种之间数千个基因的衰老依赖性顺式调节变异。然后，我们测试了这些表达变化和转录因子结合位点的种间序列变异之间的相关性。在出现的候选衰老调节因子，我们选择了一个研究很少的细胞周期因子，上游刺激因子2（USF 2），分子验证。在急性辐射实验中，缺乏USF 2的细胞损害了DNA损伤修复和反应。没有USF 2的长期衰老培养物安装了一个夸张的衰老调节程序-关闭细胞周期和DNA修复途径，并比野生型更贪婪地增加细胞因子表达。我们解释这些发现的模型下的促修复，抗衰老的调节功能USF 2。我们的研究为细胞衰老的机制提供了新的见解，并为基于自然变异的调节剂筛选提供了有效的概念证明。
Cellular senescence is a program of cell cycle arrest, apoptosis resistance, and cytokine release induced by stress exposure in metazoan cells. Landmark studies in laboratory mice have characterized a number of master senescence regulators, including p16INK4a, p21, NF-κB, p53, and C/EBPβ. To discover other molecular players in senescence, we developed a screening approach to harness the evolutionary divergence between mouse species. We found that primary cells from the Mediterranean mouse Mus spretus, when treated with DNA damage to induce senescence, produced less cytokine and had less-active lysosomes than cells from laboratory Mus musculus. We used allele-specific expression profiling to catalog senescence-dependent cis-regulatory variation between the species at thousands of genes. We then tested for correlation between these expression changes and interspecies sequence variants in the binding sites of transcription factors. Among the emergent candidate senescence regulators, we chose a little-studied cell cycle factor, upstream stimulatory factor 2 (USF2), for molecular validation. In acute irradiation experiments, cells lacking USF2 had compromised DNA damage repair and response. Longer-term senescent cultures without USF2 mounted an exaggerated senescence regulatory program—shutting down cell cycle and DNA repair pathways, and turning up cytokine expression, more avidly than wild-type. We interpret these findings under a model of pro-repair, anti-senescence regulatory function by USF2. Our study affords new insights into the mechanisms by which cells commit to senescence, and serves as a validated proof of concept for natural variation-based regulator screens.
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影响因子：
14.9
作者：
Gene Ontology Consortium
通讯作者：
Gene Ontology Consortium
影响因子：
7.7
作者：
Chan M;Yuan H;Soifer I;Maile TM;Wang RY;Ireland A;O'Brien JJ;Goudeau J;Chan LJG;Vijay T;Freund A;Kenyon C;Bennett BD;McAllister FE;Kelley DR;Roy M;Cohen RL;Levinson AD;Botstein D;Hendrickson DG
通讯作者：
Hendrickson DG
影响因子：
3.7
作者：
Coppé JP;Patil CK;Rodier F;Krtolica A;Beauséjour CM;Parrinello S;Hodgson JG;Chin K;Desprez PY;Campisi J
通讯作者：
Campisi J
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
14.9
作者：
Casella, Gabriel;Munk, Rachel;Gorospe, Myriam
通讯作者：
Gorospe, Myriam