Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions.
Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions.
复制标题
DOI：
10.1038/s41467-021-26862-z
复制
发表时间：
2021-12-13
影响因子：
16.6
通讯作者：
Akbarian S
中科院分区：
文献类型：
--
作者：
Chandrasekaran S;Espeso-Gil S;Loh YE;Javidfar B;Kassim B;Zhu Y;Zhang Y;Dong Y;Bicks LK;Li H;Rajarajan P;Peter CJ;Sun D;Agullo-Pascual E;Iskhakova M;Estill M;Lesch BJ;Shen L;Jiang Y;Akbarian S
成熟神经元中与重复序列丰富和染色体构象相关的调控机制仍未被探索。在这里，我们绘制了成年小鼠大脑皮层中细胞类型特异性染色质结构域的组织，并报道了内源性逆转录病毒2 （ERV2）重复序列在神经元特异性异色B2NeuN+巨酶缩放亚室中的强富集。野生SPRET/EiJ（小家鼠）和实验室近交C57BL/6J（小家鼠）的单分子长读测序和比较Hi-C染色体接触图谱揭示了神经元重构跟踪小鼠种系中ERV2的近期扩增，在小家鼠中持续插入的位点上B2NeuN+接触频率显著增加。逆转录转座子沉默子Kmt1e/Setdb1的神经元消融触发B2NeuN+解体和重新连接，与细胞应激反应基因富集的开放染色质结构域一起，伴随着严重的神经炎症和树突浸润的前病毒组装。我们得出的结论是，神经元巨酶规模的染色体结构包括一个进化适应的异色组织，一旦受到扰动，就会导致转录失调并释放具有强烈神经元倾向的ERV2原病毒。富重复序列在高等真核生物三维基因组结构中发挥作用；然而，这在脑细胞中仍未被探索。在这里，作者表明内源性逆转录病毒（ERV）序列的上调与大脑中3D结构的变化有关，这也通过与近期逆转录转座子扩增的小鼠品系的比较观察到。
Regulatory mechanisms associated with repeat-rich sequences and chromosomal conformations in mature neurons remain unexplored. Here, we map cell-type specific chromatin domain organization in adult mouse cerebral cortex and report strong enrichment of Endogenous Retrovirus 2 (ERV2) repeat sequences in the neuron-specific heterochromatic B2NeuN+ megabase-scaling subcompartment. Single molecule long-read sequencing and comparative Hi-C chromosomal contact mapping in wild-derived SPRET/EiJ (Mus spretus) and laboratory inbred C57BL/6J (Mus musculus) reveal neuronal reconfigurations tracking recent ERV2 expansions in the murine germline, with significantly higher B2NeuN+ contact frequencies at sites with ongoing insertions in Mus musculus. Neuronal ablation of the retrotransposon silencer Kmt1e/Setdb1 triggers B2NeuN+ disintegration and rewiring with open chromatin domains enriched for cellular stress response genes, along with severe neuroinflammation and proviral assembly with infiltration of dendrites . We conclude that neuronal megabase-scale chromosomal architectures include an evolutionarily adaptive heterochromatic organization which, upon perturbation, results in transcriptional dysregulation and unleashes ERV2 proviruses with strong neuronal tropism. Repeat-rich sequences play a role in 3D genome architecture in higher eukaryotes; however, this remains unexplored in brain cells. Here, the authors show that upregulation of endogenous retroviral (ERV) sequences is linked to changes in the 3D structure in the brain, which is also observed by comparison of mouse strains with recent retrotransposon expansion.
登录
查看更多内容
影响因子：
4.5
作者：
de Koning AP;Gu W;Castoe TA;Batzer MA;Pollock DD
通讯作者：
Pollock DD
影响因子：
30.8
作者：
Jiang Y;Loh YE;Rajarajan P;Hirayama T;Liao W;Kassim BS;Javidfar B;Hartley BJ;Kleofas L;Park RB;Labonte B;Ho SM;Chandrasekaran S;Do C;Ramirez BR;Peter CJ;C W JT;Safaie BM;Morishita H;Roussos P;Nestler EJ;Schaefer A;Tycko B;Brennand KJ;Yagi T;Shen L;Akbarian S
通讯作者：
Akbarian S
影响因子：
7.1
作者：
Garson, Jeremy A.;Usher, Louise;McCormick, Adele L.
通讯作者：
McCormick, Adele L.
影响因子：
4.8
作者：
Espeso-Gil S;Holik AZ;Bonnin S;Jhanwar S;Chandrasekaran S;Pique-Regi R;Albaigès-Ràfols J;Maher M;Permanyer J;Irimia M;Friedländer MR;Pons-Espinal M;Akbarian S;Dierssen M;Maass PG;Hor CN;Ossowski S
通讯作者：
Ossowski S
影响因子：
64.5
作者：
Bonev B;Mendelson Cohen N;Szabo Q;Fritsch L;Papadopoulos GL;Lubling Y;Xu X;Lv X;Hugnot JP;Tanay A;Cavalli G
通讯作者：
Cavalli G