Flatworm DNA methylation: deciphering the mark and characterising the machinery.

扁虫 DNA 甲基化：破译标记并表征机器。

• 批准号: BB/K005448/1
• 负责人: Karl Hoffmann
• 金额: $ 58.34万
• 依托单位: Aberystwyth University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK005448%2F1
• 关键词: Flatworm; DNA; methylation; deciphering; mark

We are all familiar with the subject of genetics, which describes how the fundamental unit of inheritance (the gene) is passed on from parent to offspring. Changes in the underlying DNA sequence that make up our inherited genes help explain why differences (eye colour, eye shape, chin size, etc.) in our outward appearance (phenotype) occur.However, genetics cannot fully explain the wide-ranging phenotypic diversity exhibited by all organisms on this planet. To do so in a systematic manner, we also have to consider another type of inheritance system called epigenetics. Epigenetics is the study of inherited changes in gene function (leading to different phenotypes) that cannot be explained by changes in the underlying DNA sequence of the gene. In other words, epigenetics attempts to explain everything that genetics cannot. One particular type of epigenetic process responsible for inherited changes in phenotype is facilitated by DNA methylation. Loss of DNA methylation regulation has been extensively studied in humans and is associated with cancer, obesity, immunodeficiencies and intellectual disabilities. Recent studies have additionally demonstrated that heritable DNA methylation patterns are influenced by our interaction with environmental (chemicals, drugs, etc.) factors. However, very little is known about DNA methylation or the processes that regulate it in other animal systems, especially invertebrates.Flatworms are a tremendously important invertebrate group (within the phylum Platyhelminthes) responsible for many economically- and biomedically-relevant parasitic diseases. These parasitic invertebrates undergo extensive developmental changes throughout their complicated lifecycles, which often involves interaction with more than one host or environment. Does environmentally influenced DNA methylation contribute to the success of parasites like these? If so, how does this occur and what genes are targeted by this epigenetic mechanism?Working in Aberystwyth, we will apply state of the art molecular biology tools to try and understand how DNA methylation regulates flatworm development. We have already found that DNA methylation is present in all three classes (Trematoda, Cestoda and Monogenea) of parasitic platyhelminth and that the enzymes responsible for these genome modifications are highly conserved. Using a model platyhelminth (Schistosoma mansoni), our project aims to further characterise the enzyme responsible for flatworm DNA methylation and to identify the genes specifically targeted by the DNA methylation machinery. By doing so in a synergistic manner, we expect to discover new roles for this epigenetic process during animal evolution. This information may eventually lead to novel ways to combat parasitic diseases.

我们都熟悉遗传学的主题，它描述了遗传的基本单位（基因）是如何从父母传给后代的。构成我们遗传基因的潜在DNA序列的变化有助于解释为什么差异（眼睛颜色，眼睛形状，下巴大小等）然而，遗传学不能完全解释这个星球上所有生物体所表现出的广泛的表型多样性。为了以系统的方式做到这一点，我们还必须考虑另一种称为表观遗传学的遗传系统。表观遗传学是研究基因功能的遗传变化（导致不同的表型），这些变化不能通过基因的潜在DNA序列的变化来解释。换句话说，表观遗传学试图解释遗传学无法解释的一切。DNA甲基化促进了一种特殊类型的表观遗传过程，该过程负责表型的遗传变化。DNA甲基化调控的丧失已在人类中得到广泛研究，并与癌症、肥胖、免疫缺陷和智力残疾有关。最近的研究还表明，遗传的DNA甲基化模式受到我们与环境（化学品，药物等）相互作用的影响。因素然而，很少有人知道DNA甲基化或在其他动物系统，特别是无脊椎动物的调控过程。扁形虫是一个非常重要的无脊椎动物群体（在门扁形动物）负责许多经济和生物医学相关的寄生虫病。这些寄生无脊椎动物在其复杂的生命周期中经历了广泛的发育变化，这通常涉及与一个以上的宿主或环境的相互作用。受环境影响的DNA甲基化是否有助于这些寄生虫的成功？如果是这样，这是如何发生的，什么基因是由这种表观遗传机制的目标？在阿伯里斯特威斯工作，我们将应用最先进的分子生物学工具，试图了解DNA甲基化如何调节扁形虫的发展。我们已经发现，DNA甲基化存在于所有三个类（吸虫，绦虫和单殖吸虫）的寄生性扁形动物和酶负责这些基因组修饰是高度保守的。我们的项目使用一个模型扁形动物（血吸虫mansoni），旨在进一步研究负责扁形虫DNA甲基化的酶，并确定DNA甲基化机制特异性靶向的基因。通过以协同的方式这样做，我们希望在动物进化过程中发现这种表观遗传过程的新作用。这些信息可能最终导致对抗寄生虫病的新方法。

项目成果

(Epi)genetic Inheritance in Schistosoma mansoni: A Systems Approach.

• DOI: 10.1016/j.pt.2016.12.002
• 发表时间: 2017-04
• 期刊: Trends in parasitology
• 影响因子: 9.6
• 作者: Cosseau C;Wolkenhauer O;Padalino G;Geyer KK;Hoffmann KF;Grunau C
• 通讯作者: Grunau C

Methyl-CpG-binding (SmMBD2/3) and chromobox (SmCBX) proteins are required for neoblast proliferation and oviposition in the parasitic blood fluke Schistosoma mansoni.

• DOI: 10.1371/journal.ppat.1007107
• 发表时间: 2018-06
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Geyer KK;Munshi SE;Whiteland HL;Fernandez-Fuentes N;Phillips DW;Hoffmann KF
• 通讯作者: Hoffmann KF

The anti-fecundity effect of 5-azacytidine (5-AzaC) on Schistosoma mansoni is linked to dis-regulated transcription, translation and stem cell activities.

• DOI: 10.1016/j.ijpddr.2018.03.006
• 发表时间: 2018-08
• 期刊: International journal for parasitology. Drugs and drug resistance
• 作者: Geyer KK;Munshi SE;Vickers M;Squance M;Wilkinson TJ;Berrar D;Chaparro C;Swain MT;Hoffmann KF
• 通讯作者: Hoffmann KF

Corrigendum: Whole genome analysis of a schistosomiasis-transmitting freshwater snail.

叉齿：血吸虫病传播的淡水蜗牛的全基因组分析。

• DOI: 10.1038/ncomms16153
• 发表时间: 2017-08-23
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Adema CM;Hillier LW;Jones CS;Loker ES;Knight M;Minx P;Oliveira G;Raghavan N;Shedlock A;do Amaral LR;Arican-Goktas HD;Assis JG;Baba EH;Baron OL;Bayne CJ;Bickham-Wright U;Biggar KK;Blouin M;Bonning BC;Botka C;Bridger JM;Buckley KM;Buddenborg SK;Lima Caldeira R;Carleton J;Carvalho OS;Castillo MG;Chalmers IW;Christensens M;Clifton S;Cosseau C;Coustau C;Cripps RM;Cuesta-Astroz Y;Cummins SF;Di Stefano L;Dinguirard N;Duval D;Emrich S;Feschotte C;Feyereisen R;FitzGerald P;Fronick C;Fulton L;Galinier R;Gava SG;Geusz M;Geyer KK;Giraldo-Calderón GI;de Souza Gomes M;Gordy MA;Gourbal B;Grunau C;Hanington PC;Hoffmann KF;Hughes D;Humphries J;Jackson DJ;Jannotti-Passos LK;de Jesus Jeremias W;Jobling S;Kamel B;Kapusta A;Kaur S;Koene JM;Kohn AB;Lawson D;Lawton SP;Liang D;Limpanont Y;Liu S;Lockyer AE;Lovato TAL;Ludolf F;Magrini V;McManus DP;Medina M;Misra M;Mitta G;Mkoji GM;Montague MJ;Montelongo C;Moroz LL;Munoz-Torres MC;Niazi U;Noble LR;Oliveira FS;Pais FS;Papenfuss AT;Peace R;Pena JJ;Pila EA;Quelais T;Raney BJ;Rast JP;Rollinson D;Rosse IC;Rotgans B;Routledge EJ;Ryan KM;Scholte LLS;Storey KB;Swain M;Tennessen JA;Tomlinson C;Trujillo DL;Volpi EV;Walker AJ;Wang T;Wannaporn I;Warren WC;Wu XJ;Yoshino TP;Yusuf M;Zhang SM;Zhao M;Wilson RK
• 通讯作者: Wilson RK

The repositioning of epigenetic probes/inhibitors identifies new anti-schistosomal lead compounds and chemotherapeutic targets.

表观遗传探针/抑制剂的重新定位确定了新的抗血吸虫先导化合物和化疗靶点。

• DOI: 10.1371/journal.pntd.0007693
• 发表时间: 2019
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Whatley KCL