Cell｜表觀基因組的代謝調(diào)控驅(qū)動致死性小兒室管膜瘤

導(dǎo)語：2020年5月22日犀呼，來自加拿大患病兒童醫(yī)院的Kulandaimanuvel Antony Michealraj等在Cell上發(fā)表了題為“Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma”的研究文章，該研究通過對PFA型室管膜瘤的組織及原代細(xì)胞進(jìn)行代謝組學(xué)及表觀組學(xué)等相關(guān)研究预茄，揭示了PFA型室管膜瘤在低氧條件下能夠保持生長跌榔，與特定的代謝物相關(guān)，它們能夠影響H3K27位點去除甲基化庸娱、增加去甲基化及乙蹩姓ǎ化等表觀遺傳狀態(tài)赃额。PFA能夠保持低水平的H3K27me3，但是抑制H3K27甲基化又能夠干擾PFA型腫瘤生長叫确。因此跳芳，靶向代謝/表觀遺傳組可能成為PFA型室管膜瘤的治療靶點。

背景

PFA型室管膜瘤見于胎兒和幼兒竹勉，是室管膜瘤中最為普遍的一種飞盆。目前主要通過神經(jīng)外科切除加上放療進(jìn)行治療，大多化療試驗失敗次乓。

不同于其他腫瘤吓歇，PFA型室管膜瘤幾乎沒有單核苷酸多態(tài)性或重復(fù)數(shù)量變異，但是它表現(xiàn)有表觀遺傳狀態(tài)異常票腰。如與H3K27低甲基化相關(guān)的EZHIP或H3F3A K27突變城看。

PFA型室管膜瘤的研究受阻于缺乏細(xì)胞系、移植器官或動物模型丧慈。該研究組前期工作揭示了后腦低氧微環(huán)境為PFA型室管膜瘤的譜系發(fā)育提供了條件析命，且PFA型室管膜瘤表現(xiàn)出低氧轉(zhuǎn)錄組特征。因此逃默，作者猜測低氧的代謝微環(huán)境可能通過中間代謝組對表觀組產(chǎn)生影響鹃愤，從而促進(jìn)PFA型室管膜瘤發(fā)育。

關(guān)鍵科學(xué)問題

低氧的代謝微環(huán)境是否通過中間代謝組對表觀組產(chǎn)生影響完域，從而促進(jìn)PFA型室管膜瘤發(fā)育软吐？

結(jié)果

Fig 1：PFA型室管膜瘤的維持受控于低氧條件。

Fig 2：PFA型室管膜瘤具有獨特的代謝譜和組蛋白低甲基化特征吟税。

Fig 3：低氧條件促使SAM缺陷凹耙，從而干擾PRC2介導(dǎo)的甲基化，并維持PFA型室管膜瘤中的H3K27低甲基化狀態(tài)肠仪。

Fig 4：低氧條件通過增加谷氨酰胺來源的a-KG含量來維持PFA型室管膜瘤中的組蛋白去甲基化活性

Fig 5：低氧條件驅(qū)動反向TCA循環(huán)活性來增加PFA型室管膜瘤中K27乙跣けВ化。

Fig 6：矛盾地异旧，抑制PRC2復(fù)合物能表現(xiàn)出對PFA型室管膜瘤的抑制效果意述。

Fig 7：后腦PFA起源的膠質(zhì)譜系在正常發(fā)育過程中表現(xiàn)出低氧特征。

討論

要判斷PFA細(xì)胞的獨特代謝表型是否是反映了起源細(xì)胞來源還是后期發(fā)育獲得需要分離起源細(xì)胞并對其進(jìn)行研究吮蛹。

代謝因子荤崇，包括急性或慢性缺氧，對PFA型室管膜瘤發(fā)育過程的具體作用需要通過模型器官進(jìn)行體內(nèi)探究潮针。

總結(jié)

Kulandaimanuvel Antony Michealraj, et al., Cell (2020)

低氧的代謝微環(huán)境通過影響中間代謝物术荤，對表觀組產(chǎn)生影響，維持H3K27位點的低甲基化及高乙趺颗瘢化狀態(tài)瓣戚，從而促進(jìn)PFA型室管膜瘤的生長端圈。

通訊作者

Michael D. Taylor

Michael D. Taylor

The Hospital for Sick Children：Neurosurgeon，Neurosurgery

Research Institute：

The Arthur and Sonia Labatt Brain Tumour Research Centre：Principal Investigator带兜；

Developmental & Stem Cell Biology：Senior Scientist

University of Toronto：Professor枫笛，Departments of Surgery and Laboratory Medicine and Pathobiology

主要經(jīng)歷：

1994：The University of Western Ontario，MD刚照；

1994-2003：University of Toronto Neurosurgery，residency喧兄；

1998-2002：PhD in Molecular Pathology at the University of Toronto无畔；

2004：The Hospital for Sick Children (SickKids), Division of Neurosurgery；

Clinical Care Activities

paediatric neurosurgeon at SickKids.

Research Interests

1吠冤，Understanding molecular genetics of medulloblastoma and ependymom浑彰；

2，Devise novel, more effective treatment strategies of medulloblastoma and ependymom拯辙；

3郭变，Identification and characterization of mutations in established paediatric medulloblastomas；

4涯保，Using tools from functional genomics to determine how a normal cerebellar cell can be turned into a medulloblastoma cell诉濒；

5，Identification and characterization of the mutations in established paediatric ependymomas夕春；

6未荒，Using tools from functional genomics to determine how a normal radial glial cell can be turned into an ependymoma cell.

Jeremy N. Rich

Jeremy N. Rich

UC San Diego Health，Neuro-oncologist及志，Professor of Medicine片排。

Fellowship：Duke University, School of Medicine, Durham, NC

Master's Degrees：Baldwin Wallace University, Berea, OH；Duke University School of Medicine, Durham, NC

Medical Degree：Duke University, School of Medicine, Durham, NC

Residency：Johns Hopkins School of Medicine, Baltimore, MD

Sameer Agnihotri

Sameer Agnihotri, PhD

University of Pittsburgh School of Medicine速侈，Associate Professor率寡；Director, Brain Tumor Biology and Therapy Lab。

Education & Training：

BSc, (hons), Biology, University of Toronto, 2005

PhD, Medical Biophysics, University of Toronto, 2011

Fellowship, Hospital for Sick Children, Toronto, 2016

Fellowship, Princess Margaret Cancer Centre, Toronto, 2016

Specialized Areas of Interest：

Pediatric and adult high-grade gliomas

Stephen C. Mack

Stephen C. Mack, PhD

Assistant Professor, Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine倚搬。

Education：

Cleveland Clinic冶共，F(xiàn)ellowship，Cancer Genetics and Epigenetics潭枣，2017比默；

University of Toronto，PhD盆犁，Doctor of Philosophy, Laboratory Medicine and Pathobiology命咐，2014；

University of Toronto谐岁，Bachelors醋奠，Bachelor of Science, Laboratory Medicine and Pathobiology榛臼，2006。

Research：

1. Delineating the molecular subgroups of posterior fossa ependymoma. (Witt* and Mack* et al., Cancer Cell, 2011)

2. Mapping the mutational landscape of posterior fossa ependymoma (Mack et al., Nature., 2014)

3. Defining the active regulatory programs of ependymal tumors (Mack et al., Nature., 2017)

參考資料

http://www.sickkids.ca/AboutSickKids/Directory/People/T/Michael-D-Taylor.html

https://providers.ucsd.edu/details/32908/jeremy-rich

https://www.neurosurgery.pitt.edu/people/sameer-agnihotri

https://www.texaschildrens.org/research/laboratories/stephen-christopher-mack-phd