AbstractSNCAIP duplication may promote Group 4 medulloblastoma via induction of PRDM6, a poorly characterized member of the PRDF1 and RIZ1 homology domain-containing (PRDM) family of transcription factors. Here, we investigated the function of PRDM6 in human hindbrain neuroepithelial stem cells and tested PRDM6 as a driver of Group 4 medulloblastoma.

摘要SNCAIP复制可能通过诱导PRDM6促进第4组髓母细胞瘤，PRDM6是PRDF1和RIZ1同源结构域（PRDM）转录因子家族的一个特征不佳的成员。在这里，我们研究了PRDM6在人后脑神经上皮干细胞中的功能，并测试了PRDM6作为第4组髓母细胞瘤的驱动因素。

We report that human PRDM6 localizes predominantly to the nucleus, where it causes widespread repression of chromatin accessibility and complex alterations of gene expression patterns. Genome-wide mapping of PRDM6 binding reveals that PRDM6 binds to chromatin regions marked by histone H3 lysine 27 trimethylation that are located within, or proximal to, genes.

我们报告说，人类PRDM6主要定位于细胞核，在那里它导致染色质可及性的广泛抑制和基因表达模式的复杂改变。PRDM6结合的全基因组图谱显示，PRDM6与位于基因内或基因附近的组蛋白H3赖氨酸27三甲基化标记的染色质区域结合。

Moreover, we show that PRDM6 expression in neuroepithelial stem cells promotes medulloblastoma. Surprisingly, medulloblastomas derived from PRDM6-expressing neuroepithelial stem cells match human Group 3, but not Group 4, medulloblastoma. We conclude that PRDM6 expression has oncogenic potential but is insufficient to drive Group 4 medulloblastoma from neuroepithelial stem cells.

此外，我们显示神经上皮干细胞中的PRDM6表达促进髓母细胞瘤。令人惊讶的是，源自表达PRDM6的神经上皮干细胞的髓母细胞瘤与人类第3组相匹配，但与第4组髓母细胞瘤不匹配。我们得出结论，PRDM6表达具有致癌潜力，但不足以从神经上皮干细胞中驱动第4组髓母细胞瘤。

We propose that both PRDM6 and additional factors, such as specific cell-of-origin features, are required for Group 4 medulloblastoma. Given the lack of PRDM6 expression in normal tissues and its oncogenic potential shown here, we suggest that PRDM6 inhibition may have therapeutic value in PRDM6-expressing medulloblastomas..

我们建议第4组髓母细胞瘤需要PRDM6和其他因素，例如特定的起源细胞特征。鉴于正常组织中缺乏PRDM6表达及其致癌潜力，我们建议PRDM6抑制可能对表达PRDM6的髓母细胞瘤具有治疗价值。。

IntroductionMedulloblastoma, a malignant childhood tumor of the cerebellum, represents a clinically and molecularly heterogeneous cancer originating from aberrant hindbrain development1,2,3,4. The cellular origins and genetic drivers of WNT and SHH medulloblastomas are relatively well characterized but drivers of Group 3 and 4 medulloblastoma remain unclear.

引言髓母细胞瘤是一种小脑恶性儿童肿瘤，代表了一种源自异常后脑发育的临床和分子异质性癌症1,2,3,4。WNT和SHH髓母细胞瘤的细胞起源和遗传驱动因素相对较好，但第3组和第4组髓母细胞瘤的驱动因素仍不清楚。

Especially Group 4 medulloblastomas show a complex range of molecular aberrations and clinical outcomes4,5.One of the most characteristic alterations of Group 4 medulloblastoma is the expression of PRDM6, which occurs in 17% of all Group 4 medulloblastoma cases1,4. Moreover, PRDM6-expressing Group 4 medulloblastomas often show other alterations, such as aberrant expression of the MYCN oncogene5.

特别是第4组髓母细胞瘤显示出复杂的分子畸变和临床结果[4,5]。第4组髓母细胞瘤最具特征性的改变之一是PRDM6的表达，其发生在所有第4组髓母细胞瘤病例中的17%1,4。此外，表达PRDM6的第4组髓母细胞瘤通常表现出其他改变，例如MYCN癌基因5的异常表达。

The upregulation of PRDM6 expression in Group 4 medulloblastoma is thought to occur via enhancer hijacking caused by tandem duplication of SNCAIP, which is located approximately 600 kb upstream of PRDM64. Although other genes are located within the topologically-associated domains of SNCAIP, only PRDM6 shows robust upregulation4.

第4组髓母细胞瘤中PRDM6表达的上调被认为是通过SNCAIP串联重复引起的增强子劫持而发生的，SNCAIP位于PRDM64上游约600 kb。尽管其他基因位于SNCAIP的拓扑相关结构域内，但只有PRDM6显示出强大的上调4。

PRDM6 is a poorly characterized member of the PRDF1 and RIZ1 homology domain-containing (PRDM) family of transcription factors that possess histone lysine methyltransferase activities through their catalytic SET domain6. However, the enzymatic activity and molecular function of human PRDM6 is unclear.

PRDM6是PRDF1和RIZ1同源结构域（PRDM）转录因子家族的一个特征不佳的成员，该家族通过其催化SET结构域6具有组蛋白赖氨酸甲基转移酶活性。然而，人类PRDM6的酶活性和分子功能尚不清楚。

Based on findings in other species, PRDM6 is currently classified as a pseudo-methyltransferase that may interact with the methyltransferase G9a and corepressors to indirectly affect the methylation status of histone H3 lysine 9 and histone H4 lysine 206,7,8.Several PRDM proteins have been implicated in cellular processes related to stem cell maintenance or differentiation in the central nervous system.

。

Data availability

数据可用性

All next-generation sequencing datasets generated as part of this study have been deposited to the NCBI Gene Expression Omnibus repository under accession number GSE243558.

作为本研究的一部分生成的所有下一代测序数据集已以登录号GSE243558保存到NCBI Gene Expression Omnibus repository。

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R Core Team. R: A Language and Environment for Statistical Computing. (R Foundation for Statistical Computing, Vienna, Austria, 2021).Download referencesAcknowledgementsThis work was supported by the UCSF Brain Tumor SPORE Career Development Program, the UCSF Program for Breakthrough Biomedical Research (which is partially funded by the Sandler Foundation), the Shurl and Kay Curci Foundation, and NIH R01 AG064363 (B.S).

R核心团队。R： 用于统计计算的语言和环境。（R统计计算基金会，维也纳，奥地利，2021年）。下载参考文献致谢这项工作得到了加州大学旧金山分校脑肿瘤孢子职业发展计划，加州大学旧金山分校突破性生物医学研究计划（部分由桑德勒基金会资助），舒尔和凯·库奇基金会以及NIH R01 AG064363（B.S）的支持。

B.S. was a Kimmel Scholar of The Sidney Kimmel Foundation and holds the Suzanne Marie Haderle and Robert Vincent Haderle Endowed Chair at UCSF. C.S. was supported by a PRCRP Horizon Award from the Congressionally Directed Medical Research Programs, U.S. Department of Defense. S.C. was supported by a Sullivan Postdoctoral Fellowship.

B、 。C、 美国获得了美国国防部国会医学研究计划（National Directed Medical Research Programs）颁发的PRCRP Horizon奖的支持。S、 C.得到了沙利文博士后奖学金的支持。

W.A.W acknowledges R01NS125668; R01CA159859; R01CA255369; R01NS106155 and P30CA082103. This study was further supported, in part, by the HDFCCC Laboratory for Cell Analysis Shared Resource Facility through NIH grant P30CA082103. Parts of Figure 1A and Figure 6A were created with content licensed from BioRender.Author informationAuthors and AffiliationsDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USAChristin Schmidt, Sarah Cohen, Annika Carlson, Joanna J.

W、 A.W承认R01NS125668；R01CA159859；R01CA255369；R01NS106155和P30CA082103。HDFCCC细胞分析实验室共享资源设施通过NIH拨款P30CA082103进一步支持了这项研究。图1A和图6A的部分内容是使用BioRender许可的内容创建的。作者信息作者和附属机构加利福尼亚大学旧金山分校神经外科，加利福尼亚州旧金山，美国克里斯汀·施密特，莎拉·科恩，安妮卡·卡尔森，乔安娜·J。

Phillips, William A. Weiss & Bjoern SchwerDepartment of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USABjoern SchwerEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USAChristin Schmidt, Sarah Cohen, Annika Carlson & Bjoern SchwerWeill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA, USAChristin Schmidt, Sarah Cohen, Annika Carlson, Wil.

Phillips，William A.Weiss＆Bjoern Schwer加利福尼亚大学旧金山分校细胞与分子药理学系，USABjoern Schwerelis和Edythe加利福尼亚大学旧金山分校再生医学与干细胞研究中心，USAChristin Schmidt，Sarah Cohen，Annika Carlson＆Bjoern SchwerWeill神经科学研究所，加利福尼亚大学旧金山分校，加利福尼亚州旧金山，USAChristin Schmidt，Sarah Cohen，Annika Carlson，Wil。

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PubMed Google ScholarContributionsCS and BS designed and planned the study; CS, SH, AC, SC, SW, and LW performed research; CS, BLG, JJP, PAN, WAW, and BS analyzed data; WAW and BS supervised the research; CS and BS wrote the manuscript and all authors commented on the manuscript.Corresponding authorsCorrespondence to.

PubMed谷歌学术贡献SCS和BS设计并计划了这项研究；CS，SH，AC，SC，SW和LW进行了研究；CS，BLG，JJP，PAN，WAW和BS分析数据；WAW和BS监督了这项研究；CS和BS撰写了手稿，所有作者都对手稿发表了评论。通讯作者通讯。

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Reprints and permissionsAbout this articleCite this articleSchmidt, C., Cohen, S., Gudenas, B.L. et al. PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression.

转载和许可本文引用本文Schmidt，C.，Cohen，S.，Gudenas，B.L。等人。PRDM6通过抑制染色质可及性和改变基因表达来促进髓母细胞瘤。

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