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Cancer Cell. 2019 Jan 14;35(1):95-110.e8. doi: 10.1016/j.ccell.2018.11.014. Epub 2018 Dec 27.

Comprehensive Analysis of Chromatin States in Atypical Teratoid/Rhabdoid Tumor Identifies Diverging Roles for SWI/SNF and Polycomb in Gene Regulation.

Author information

1
Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany; Izmir Biomedicine and Genome Center, 35340 Izmir, Turkey.
2
Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
3
Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, NE2 Newcastle Upon Tyne, UK.
4
Department of Oncology, St Jude Children's Research Hospital, 38105 Memphis, USA.
5
Division of Molecular Genetics, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
6
Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
7
Department of Neuropathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
8
Department of Neuropathology, Burdenko Neurosurgical Institute, 125047 Moscow, Russia.
9
Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
10
Genome Organization & Function Research Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, 69120 Heidelberg, Germany.
11
Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, 69120 Heidelberg, Germany.
12
Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
13
Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
14
University Children's Hospital Augsburg, Swabian Children's Cancer Center, 86156 Augsburg, Germany; EU-RHAB Registry Center, 86156 Augsburg, Germany.
15
Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 38105 Memphis, TN, USA.
16
European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany.
17
Division of Molecular Genetics, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, 69120 Heidelberg, Germany.
18
Genome Organization & Function Research Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
19
Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany.
20
Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: m.kool@kitz-heidelberg.de.

Abstract

Biallelic inactivation of SMARCB1, encoding a member of the SWI/SNF chromatin remodeling complex, is the hallmark genetic aberration of atypical teratoid rhabdoid tumors (ATRT). Here, we report how loss of SMARCB1 affects the epigenome in these tumors. Using chromatin immunoprecipitation sequencing (ChIP-seq) on primary tumors for a series of active and repressive histone marks, we identified the chromatin states differentially represented in ATRTs compared with other brain tumors and non-neoplastic brain. Re-expression of SMARCB1 in ATRT cell lines enabled confirmation of our genome-wide findings for the chromatin states. Additional generation of ChIP-seq data for SWI/SNF and Polycomb group proteins and the transcriptional repressor protein REST determined differential dependencies of SWI/SNF and Polycomb complexes in regulation of diverse gene sets in ATRTs.

KEYWORDS:

EZH2; SMARCA4; SMARCB1; atypical teratoid rhabdoid tumor; chromatin states; pediatric brain tumor

PMID:
30595504
PMCID:
PMC6341227
[Available on 2020-01-14]
DOI:
10.1016/j.ccell.2018.11.014

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