Transposon Dysregulation Modulates dWnt4 Signaling to Control Germline Stem Cell Differentiation in Drosophila.
Transposon Dysregulation Modulates dWnt4 Signaling to Control Germline Stem Cell Differentiation in Drosophila.
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DOI：
10.1371/journal.pgen.1005918
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发表时间：
2016-03
期刊：
影响因子：
4.5
通讯作者：
Rangan P
中科院分区：
文献类型：
--
作者：
Upadhyay M;Martino Cortez Y;Wong-Deyrup S;Tavares L;Schowalter S;Flora P;Hill C;Nasrallah MA;Chittur S;Rangan P
生殖系干细胞（GSC）的自我更新和分化是配子持续产生所必需的。果蝇卵发生过程中GSC的分化需要通过体细胞生态位表达组蛋白甲基转移酶dSETDB1，但其在这一过程中的功能尚不清楚。在这里，我们发现dSETDB1是Wnt配体，果蝇无翅型小鼠乳腺病毒整合位点4 （dWnt4）在体细胞生态位中的表达所必需的。dWnt4信号传导作用于体细胞壁龛细胞，促进其包封GSC子细胞，作为分化线索。已知dSETDB1可抑制转座因子（te）以维持基因组完整性。出乎意料的是，我们发现te的独立上调也会下调dWnt4，导致GSC分化缺陷。这表明dWnt4的表达对TEs的存在很敏感。总之，我们的研究结果揭示了染色质-转座子- wnt信号轴调节干细胞的命运。每一个多细胞生物都是由干细胞维持的组织组成的，因为干细胞有自我更新和分化为终端细胞类型的能力。失去这些过程中的任何一个都可能导致衰老，向退行性疾病和癌症发展。深入了解自我更新和分化是如何被调节的，将对治疗产生巨大影响。由于各种突变体、标记物和RNAi技术的可用性，果蝇是干细胞研究的一个很好的模型系统。我们研究了雌性果蝇的卵巢，其干细胞群产生配子。产生这些配子的组织被体细胞包围，体细胞提供适当的自我更新和分化所需的信号提示。虽然这些体细胞信号调节干细胞自我更新的机制是已知的，但体细胞信号如何调节分化仍不清楚。在这里，我们已经确定了转座子，自私的遗传元件，调节体细胞中的dWnt4表达。我们证明了dWnt4通过调节粘附体连接蛋白来促进干细胞子细胞的体细胞包封，从而促进分化。转座子与癌症有关，因此，确定转座子如何调节分化所必需的基因可以为其在癌症中的作用提供新的视角。
Germline stem cell (GSC) self-renewal and differentiation are required for the sustained production of gametes. GSC differentiation in Drosophila oogenesis requires expression of the histone methyltransferase dSETDB1 by the somatic niche, however its function in this process is unknown. Here, we show that dSETDB1 is required for the expression of a Wnt ligand, Drosophila Wingless type mouse mammary virus integration site number 4 (dWnt4) in the somatic niche. dWnt4 signaling acts on the somatic niche cells to facilitate their encapsulation of the GSC daughter, which serves as a differentiation cue. dSETDB1 is known to repress transposable elements (TEs) to maintain genome integrity. Unexpectedly, we found that independent upregulation of TEs also downregulated dWnt4, leading to GSC differentiation defects. This suggests that dWnt4 expression is sensitive to the presence of TEs. Together our results reveal a chromatin-transposon-Wnt signaling axis that regulates stem cell fate. Every multicellular organism is made up of tissues that are maintained by stem cells, due to their capacity to both self-renew and differentiate into terminal cell types. Loss of either of these processes can lead to aging, progression towards degenerative diseases and cancers. Insight into how self-renewal and differentiation are regulated will have tremendous therapeutic impact. Drosophila is an excellent model system for stem cell study due to the availability of various mutants, markers and RNAi technology. We study the ovaries of the female Drosophila, whose stem cell population gives rise to gametes. The tissue from which these gametes arise is surrounded by somatic cells, which provide signaling cues required for proper self-renewal and differentiation. While the mechanisms by which these somatic signals regulate stem cell self-renewal is known, how somatic cues regulate differentiation remains unclear. Here, we have identified that transposons, selfish genetic elements, modulate dWnt4 expression in the somatic cells. We demonstrate that dWnt4 promotes the somatic encapsulation of the stem cell daughter by regulating adherens junction proteins, thereby promoting differentiation. Transposons have been linked to cancers, and therefore establishing how transposons regulate genes essential for differentiation can provide new perspectives on their role in cancer.