Multilayered gene control drives timely exit from the stem cell state in uncommitted progenitors during Drosophila asymmetric neural stem cell division.
Multilayered gene control drives timely exit from the stem cell state in uncommitted progenitors during Drosophila asymmetric neural stem cell division.
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DOI：
10.1101/gad.320333.118
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发表时间：
2018-12-01
影响因子：
10.5
通讯作者：
Lee CY
中科院分区：
文献类型：
--
作者：
Komori H;Golden KL;Kobayashi T;Kageyama R;Lee CY
Komori等人。证明了在果蝇神经干细胞谱系中，多层基因调控系统终止了未承诺干细胞后代在所有水平上的自我更新基因活性。自我更新基因通过阻止干细胞分化的承诺来维持干细胞处于未分化状态。干细胞不对称分裂后自我更新基因活性的强大失活使未承诺的干细胞后代退出未分化状态，并启动分化承诺。然而，在未承诺的干细胞后代中，如何在mRNA和蛋白质水平上同步终止自我更新基因活性尚不清楚。我们证明，在果蝇神经干细胞谱系中，多层基因调控系统终止了未承诺干细胞后代在所有水平上的自我更新基因活性。我们发现，RNA结合蛋白脑瘤(Brat)通过将死烯基化机制招募到3‘非翻译区(UTR)来靶向自我更新基因Deadpan(Dpn)的转录本。此外，我们还发现了一种核蛋白INSENSIVE，它可以补充库林介导的蛋白分解，通过蛋白质隔离限制活性DPN的水平，从而有效地灭活DPN的活性。自我更新基因的转录后控制和转录控制之间的协同作用促使未承诺的祖细胞适时退出干细胞状态。我们提出的多层基因调控系统可以广泛应用于所有干细胞系的出干控制。
Komori et al. demonstrate that a multilayered gene regulation system terminates self-renewal gene activity at all levels in uncommitted stem cell progeny in the fly neural stem cell lineage. Self-renewal genes maintain stem cells in an undifferentiated state by preventing the commitment to differentiate. Robust inactivation of self-renewal gene activity following asymmetric stem cell division allows uncommitted stem cell progeny to exit from an undifferentiated state and initiate the commitment to differentiate. Nonetheless, how self-renewal gene activity at mRNA and protein levels becomes synchronously terminated in uncommitted stem cell progeny is unclear. We demonstrate that a multilayered gene regulation system terminates self-renewal gene activity at all levels in uncommitted stem cell progeny in the fly neural stem cell lineage. We found that the RNA-binding protein Brain tumor (Brat) targets the transcripts of a self-renewal gene, deadpan (dpn), for decay by recruiting the deadenylation machinery to the 3′ untranslated region (UTR). Furthermore, we identified a nuclear protein, Insensible, that complements Cullin-mediated proteolysis to robustly inactivate Dpn activity by limiting the level of active Dpn through protein sequestration. The synergy between post-transcriptional and transcriptional control of self-renewal genes drives timely exit from the stem cell state in uncommitted progenitors. Our proposed multilayered gene regulation system could be broadly applicable to the control of exit from stemness in all stem cell lineages.
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DOI：
10.1261/rna.062208.117
发表时间：
2017-10
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Götze M;Dufourt J;Ihling C;Rammelt C;Pierson S;Sambrani N;Temme C;Sinz A;Simonelig M;Wahle E
通讯作者：
Wahle E
影响因子：
3.7
作者：
Coumailleau F;Schweisguth F
通讯作者：
Schweisguth F
影响因子：
12.3
作者：
Laver JD;Li X;Ray D;Cook KB;Hahn NA;Nabeel-Shah S;Kekis M;Luo H;Marsolais AJ;Fung KY;Hughes TR;Westwood JT;Sidhu SS;Morris Q;Lipshitz HD;Smibert CA
通讯作者：
Smibert CA
影响因子：
4.6
作者：
Janssens, Derek H.;Komori, Hideyuki;Lee, Cheng-Yu
通讯作者：
Lee, Cheng-Yu
影响因子：
7.7
作者：
Komori, Hideyuki;Xiao, Qi;Lee, Cheng-Yu
通讯作者：
Lee, Cheng-Yu