Genome-wide analysis identifies Homothorax and Extradenticle as regulators of insulin in Drosophila Insulin-Producing cells.
Genome-wide analysis identifies Homothorax and Extradenticle as regulators of insulin in Drosophila Insulin-Producing cells.
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DOI：
10.1371/journal.pgen.1010380
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发表时间：
2022-09
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影响因子：
4.5
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中科院分区：
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果蝇胰岛素产生细胞（IPC）是果蝇胰岛素样肽（dilps）的主要产生场所，其在调节生长、发育、生殖、寿命和代谢等方面具有重要作用。为了更好地理解在IPC中活跃的信号传导途径和转录网络，我们查询了超过180个高度近交的果蝇品系的公开可用的转录组数据用于dilp表达，并使用dilp表达作为全基因组关联研究（GWAS）的输入。这导致了125个基因中与dilp表达变异相关的变异的鉴定。使用基于RNAi的方法测试了IPC中这些基因中的57个的功能。我们发现，IPC特异性耗尽大多数基因导致一个或多个dilps的表达差异。然后，我们进一步阐述了对dilp表达影响最大的候选基因之一，Homothorax，一种以其在眼睛发育中的作用而闻名的转录因子。我们发现，Homothorax和它的结合伙伴Extradenticle参与调节dilp 2，-3和-5的表达和遗传损耗的两个TF显示与减少胰岛素信号传导的表型。此外，我们提供的证据表明，其他参与眼睛发育的转录因子也在IPC中发挥作用。总之，我们表明，这种基于表达水平的GWAS方法鉴定了涉及IPC功能和dilp表达的遗传调节因子。胰岛素信号传导在许多过程中具有中心的和进化上保守的作用，包括生长、发育、生殖、寿命、应激抗性和代谢稳态。在果蝇（Drosophila melanogaster）中，脑中的胰岛素产生细胞是三种胰岛素样肽Dilp 2、Dilp-3和Dilp-5的主要来源。这三种胰岛素样肽的产生和分泌是如何被调节的仍然不完全清楚。在目前的研究中，全基因组关联研究被用来确定50个新的Dilp 2，-3和-5调节器。我们发现，最佳候选调节剂之一，Homothorax，是一个重要的调节dilp 2，-3和-5在IPC的表达，是必要的正常的全身胰岛素信号传导和调节成人的大小和发育时间。我们还表明，Hth相互作用外齿（Exd）同样需要在成人，但不是在幼虫的IPC。最后，我们表明，大多数基因的所谓的视网膜决定基因网络中的IPC和调节正常dilp 2和-5的表达。总之，这些结果确定了进一步的监管水平活跃的IPC和牵连的重组版本的先前确定的基因调控网络。
Drosophila Insulin-Producing Cells (IPCs) are the main production site of the Drosophila Insulin-like peptides or dilps which have key roles in regulating growth, development, reproduction, lifespan and metabolism. To better understand the signalling pathways and transcriptional networks that are active in the IPCs we queried publicly available transcriptome data of over 180 highly inbred fly lines for dilp expression and used dilp expression as the input for a Genome-wide association study (GWAS). This resulted in the identification of variants in 125 genes that were associated with variation in dilp expression. The function of 57 of these genes in the IPCs was tested using an RNAi-based approach. We found that IPC-specific depletion of most genes resulted in differences in expression of one or more of the dilps. We then elaborated further on one of the candidate genes with the strongest effect on dilp expression, Homothorax, a transcription factor known for its role in eye development. We found that Homothorax and its binding partner Extradenticle are involved in regulating dilp2, -3 and -5 expression and that genetic depletion of both TFs shows phenotypes associated with reduced insulin signalling. Furthermore, we provide evidence that other transcription factors involved in eye development are also functional in the IPCs. In conclusion, we showed that this expression level-based GWAS approach identified genetic regulators implicated in IPC function and dilp expression. Insulin signalling has a central and evolutionarily conserved role in many processes including growth, development, reproduction, lifespan, stress resistance and metabolic homeostasis. In the fruitfly Drosophila melanogaster insulin-producing cells in the brain are the main source of three insulin-like peptides, Dilp2, -3 and -5. How the production and secretion of these three insulin-like peptides are regulated remains incompletely understood. In the current study, genome-wide association studies were used to identify 50 novel regulators of Dilp2, -3 and -5. We show that one of the top candidate regulators, Homothorax, is an important regulator of dilp2, -3 and –5 expression in the IPCs and is necessary for normal systemic insulin signalling and regulates adult size and developmental timing. We also show that the Hth interactor Extradenticle (Exd) is equally required in the adult but not in the larval IPCs. Finally, we show that most genes of the so-called retinal determination gene network are expressed in the IPCs and regulate normal dilp2 and -5 expression. Together, these results identify further regulatory levels active in the IPCs and implicate a reshuffled version of a previously identified gene regulatory network therein.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
10.5
作者：
Bessa, J;Gebelein, B;Mann, RS
通讯作者：
Mann, RS
影响因子：
9.2
作者：
Brogiolo, W;Stocker, H;Hafen, E
通讯作者：
Hafen, E
影响因子：
9.2
作者：
Imambocus, Bibi Nusreen;Zhou, Fangmin;Soba, Peter
通讯作者：
Soba, Peter
DOI：
10.1073/pnas.1519159112
发表时间：
2015-11-03
影响因子：
11.1
作者：
Huang, Wen;Carbone, Mary Anna;Mackay, Trudy F. C.
通讯作者：
Mackay, Trudy F. C.