Cell｜表观基因组的代谢调控驱动致死性小儿室管膜瘤

导语：2020年5月22日，来自加拿大患病儿童医院的Kulandaimanuvel Antony Michealraj等在Cell上发表了题为“Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma”的研究文章，该研究通过对PFA型室管膜瘤的组织及原代细胞进行代谢组学及表观组学等相关研究，揭示了PFA型室管膜瘤在低氧条件下能够保持生长，与特定的代谢物相关，它们能够影响H3K27位点去除甲基化、增加去甲基化及乙酰化等表观遗传状态。PFA能够保持低水平的H3K27me3，但是抑制H3K27甲基化又能够干扰PFA型肿瘤生长。因此，靶向代谢/表观遗传组可能成为PFA型室管膜瘤的治疗靶点。

背景

PFA型室管膜瘤见于胎儿和幼儿，是室管膜瘤中最为普遍的一种。目前主要通过神经外科切除加上放疗进行治疗，大多化疗试验失败。

不同于其他肿瘤，PFA型室管膜瘤几乎没有单核苷酸多态性或重复数量变异，但是它表现有表观遗传状态异常。如与H3K27低甲基化相关的EZHIP或H3F3A K27突变。

PFA型室管膜瘤的研究受阻于缺乏细胞系、移植器官或动物模型。该研究组前期工作揭示了后脑低氧微环境为PFA型室管膜瘤的谱系发育提供了条件，且PFA型室管膜瘤表现出低氧转录组特征。因此，作者猜测低氧的代谢微环境可能通过中间代谢组对表观组产生影响，从而促进PFA型室管膜瘤发育。

关键科学问题

低氧的代谢微环境是否通过中间代谢组对表观组产生影响，从而促进PFA型室管膜瘤发育？

结果

Fig 1：PFA型室管膜瘤的维持受控于低氧条件。

Fig 2：PFA型室管膜瘤具有独特的代谢谱和组蛋白低甲基化特征。

Fig 3：低氧条件促使SAM缺陷，从而干扰PRC2介导的甲基化，并维持PFA型室管膜瘤中的H3K27低甲基化状态。

Fig 4：低氧条件通过增加谷氨酰胺来源的a-KG含量来维持PFA型室管膜瘤中的组蛋白去甲基化活性

Fig 5：低氧条件驱动反向TCA循环活性来增加PFA型室管膜瘤中K27乙酰化。

Fig 6：矛盾地，抑制PRC2复合物能表现出对PFA型室管膜瘤的抑制效果。

Fig 7：后脑PFA起源的胶质谱系在正常发育过程中表现出低氧特征。

讨论

• 要判断PFA细胞的独特代谢表型是否是反映了起源细胞来源还是后期发育获得需要分离起源细胞并对其进行研究。

• 代谢因子，包括急性或慢性缺氧，对PFA型室管膜瘤发育过程的具体作用需要通过模型器官进行体内探究。
  

总结

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

低氧的代谢微环境通过影响中间代谢物，对表观组产生影响，维持H3K27位点的低甲基化及高乙酰化状态，从而促进PFA型室管膜瘤的生长。

通讯作者

• 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；
Developmental & Stem Cell Biology：Senior Scientist
University of Toronto：Professor，Departments of Surgery and Laboratory Medicine and Pathobiology

主要经历：
1994：The University of Western Ontario，MD；
1994-2003：University of Toronto Neurosurgery，residency；
1998-2002：PhD in Molecular Pathology at the University of Toronto；
2004：The Hospital for Sick Children (SickKids), Division of Neurosurgery；

Clinical Care Activities
paediatric neurosurgeon at SickKids.

Research Interests
1，Understanding molecular genetics of medulloblastoma and ependymom；
2，Devise novel, more effective treatment strategies of medulloblastoma and ependymom；
3，Identification and characterization of mutations in established paediatric medulloblastomas；
4，Using tools from functional genomics to determine how a normal cerebellar cell can be turned into a medulloblastoma cell；
5，Identification and characterization of the mutations in established paediatric ependymomas；
6，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，Professor of Medicine。

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，Associate Professor；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。

Education：
Cleveland Clinic，Fellowship，Cancer Genetics and Epigenetics，2017；
University of Toronto，PhD，Doctor of Philosophy, Laboratory Medicine and Pathobiology，2014；
University of Toronto，Bachelors，Bachelor of Science, Laboratory Medicine and Pathobiology，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)

参考资料

• 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