Enhancer of polycomb coordinates multiple signaling pathways to promote both cyst and germline stem cell differentiation in the Drosophila adult testis.
Enhancer of polycomb coordinates multiple signaling pathways to promote both cyst and germline stem cell differentiation in the Drosophila adult testis.
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DOI：
10.1371/journal.pgen.1006571
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发表时间：
2017-02
期刊：
影响因子：
4.5
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Feng L;Shi Z;Chen X
干细胞存在于一个特殊的微环境中，称为小生境。干细胞中源自小生境的外在线索与内在因素之间的相互作用决定了它们的身份和活性。已知干细胞身份的维持和干细胞自我更新受染色质因子控制。在此，我们使用果蝇成年睾丸，其中有两个成人干细胞谱系，生殖干细胞（GSC）谱系和囊肿干细胞（CySC）谱系，研究染色质因子如何调节干细胞分化。我们发现染色质因子Polycomb增强子[E（Pc）]在CySC谱系中起作用，以负性控制与多种信号传导途径相关的基因的转录，包括JAK-STAT和EGF，从而促进CySC谱系中的细胞分化。E（Pc）在调节GSC谱系分化中也具有非细胞自主作用。当E（Pc）在CySC谱系中特异性失活时，在生殖细胞分化和生殖系身份的维持中都会出现缺陷。此外，在CySC谱系中损害Tip 60组蛋白乙酰转移酶活性概括了E（Pc）的功能丧失表型，表明Tip 60和E（Pc）一起起作用，与已发表的生物化学数据一致。总之，我们的研究结果表明，E（Pc）在协调果蝇睾丸中两个成体干细胞谱系之间的分化中起着核心作用。组织的维持和修复依赖于成体干细胞，成体干细胞可以分裂产生新的干细胞以及致力于成为特定细胞类型的细胞。干细胞活动需要严格控制，因为不充分或无限制的干细胞分裂可能导致组织变性或肿瘤发生。这种控制不仅取决于干细胞本身，还取决于干细胞所在的微环境。干细胞的染色质结构对决定其活性至关重要。连接干细胞与其微环境的信号通路也很重要。在这里，我们问如何染色质因子相互作用的信号通路，在确定干细胞的活动。我们使用果蝇成年睾丸作为模型系统，其中两种类型的干细胞共存并相互作用：生殖系干细胞和体细胞干细胞。我们发现，一种名为多梳增强子[E（Pc）]的染色质调节因子在体细胞中起作用，以促进生殖细胞分化并维持生殖细胞的命运。这种调节由几种信号通路介导，例如EGF和JAK-STAT通路。在体细胞中，E（Pc）还与另一种染色质调节剂组蛋白乙酰转移酶Tip 60一起起作用。E（Pc）同系物在人体中的活性不足会导致癌症。我们对E（Pc）的研究可能有助于了解其作为肿瘤抑制剂的作用。
Stem cells reside in a particular microenvironment known as a niche. The interaction between extrinsic cues originating from the niche and intrinsic factors in stem cells determines their identity and activity. Maintenance of stem cell identity and stem cell self-renewal are known to be controlled by chromatin factors. Herein, we use the Drosophila adult testis which has two adult stem cell lineages, the germline stem cell (GSC) lineage and the cyst stem cell (CySC) lineage, to study how chromatin factors regulate stem cell differentiation. We find that the chromatin factor Enhancer of Polycomb [E(Pc)] acts in the CySC lineage to negatively control transcription of genes associated with multiple signaling pathways, including JAK-STAT and EGF, to promote cellular differentiation in the CySC lineage. E(Pc) also has a non-cell-autonomous role in regulating GSC lineage differentiation. When E(Pc) is specifically inactivated in the CySC lineage, defects occur in both germ cell differentiation and maintenance of germline identity. Furthermore, compromising Tip60 histone acetyltransferase activity in the CySC lineage recapitulates loss-of-function phenotypes of E(Pc), suggesting that Tip60 and E(Pc) act together, consistent with published biochemical data. In summary, our results demonstrate that E(Pc) plays a central role in coordinating differentiation between the two adult stem cell lineages in Drosophila testes. Tissue maintenance and repair rely on adult stem cells, which can divide to generate new stem cells as well as cells committed for becoming specific cell types. Stem cell activity needs to be tightly controlled because insufficient or unlimited stem cell division may lead to tissue degeneration or tumorigenesis. This control depends not only on stem cells themselves, but also on the microenvironment where stem cells reside. The chromatin structure of stem cells is crucial to determine their activities. The signaling pathways connecting stem cells with their microenvironment is also important. Here we ask how chromatin factors interact with signaling pathways in determining stem cell activity. We use Drosophila adult testis as a model system, in which two types of stem cells co-exist and interact: germline stem cells and somatic stem cells. We find that a chromatin regulator called Enhancer of Polycomb [E(Pc)] acts in somatic cells to promote germ cell differentiation and maintain germ cell fate. This regulation is mediated by several signaling pathways, such as EGF and JAK-STAT pathways. E(Pc) also works with another chromatin regulator, the histone acetyltransferase Tip60, in somatic cells. Insufficient activity of the E(Pc) homolog in human leads to cancers. Our studies of E(Pc) may help understanding its roles as a tumor suppressor.