SMARCB1 loss activates patient-specific distal oncogenic enhancers in malignant rhabdoid tumors

Ning Qing Liu, Irene Paassen, Lars Custers, Peter Zeller, Hans Teunissen, Dilara Ayyildiz, Jiayou He, Juliane Laura Buhl, Eelco Wieger Hoving, Alexander van Oudenaarden, Elzo de Wit, Jarno Drost

Research output: Contribution to journal/periodicalArticleScientificpeer-review

1 Citation (Scopus)

Abstract

Malignant rhabdoid tumor (MRT) is a highly malignant and often lethal childhood cancer. MRTs are genetically defined by bi-allelic inactivating mutations in SMARCB1, a member of the BRG1/BRM-associated factors (BAF) chromatin remodeling complex. Mutations in BAF complex members are common in human cancer, yet their contribution to tumorigenesis remains in many cases poorly understood. Here, we study derailed regulatory landscapes as a consequence of SMARCB1 loss in the context of MRT. Our multi-omics approach on patient-derived MRT organoids reveals a dramatic reshaping of the regulatory landscape upon SMARCB1 reconstitution. Chromosome conformation capture experiments subsequently reveal patient-specific looping of distal enhancer regions with the promoter of the MYC oncogene. This intertumoral heterogeneity in MYC enhancer utilization is also present in patient MRT tissues as shown by combined single-cell RNA-seq and ATAC-seq. We show that loss of SMARCB1 activates patient-specific epigenetic reprogramming underlying MRT tumorigenesis.

Original languageEnglish
Pages (from-to)7762
JournalNature Communications
Volume14
Issue number1
DOIs
Publication statusPublished - 01 Dec 2023

Keywords

  • Humans
  • Child
  • Rhabdoid Tumor/genetics
  • SMARCB1 Protein/genetics
  • Transcription Factors/genetics
  • Mutation
  • Promoter Regions, Genetic/genetics
  • Carcinogenesis/genetics

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