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Capture of TAD reorganization endows variant patterns of gene transcription (RNA-Seq)

ABSTRACT: TAD (Topologically Associating Domain) reorganization occurs commonly in cell nucleus and contributes to gene activation and inhibition through separation or fusion of adjacent TADs. However, identification of functional genes impacted by TAD alteration and revealing of TAD-reorganization mechanism underlying gene transcription remain to be fully elucidated. Here, we firstly developed a novel approach termed Inter3D to specifically dig out genes regulated by TAD reorganization. By constructing the comprehensive TAD reorganization medicating epigenomic landscapes in tumor cells, we showed that TAD separation interrupted the intrachromosomal loop at MYL12B locus and abrogated its transcription, while TAD fusion generated the chromosomal interaction and triggered CYP27B1 activation. Our study provides a comprehensive insight into capture of TAD rearrangement-mediated gene loci and moves towards recognizing the functional role of TAD reorganization in gene transcription.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230797 | GEO | 2024/04/29

REPOSITORIES: GEO

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Project description:Neuroblastoma tumors frequently show loss of heterozygosity of chromosome 11q with a shortest region of overlap in the 11q23 region. These deletions are thought to cause inactivation of tumor suppressor genes leading to haploinsufficiency. Alternatively, micro-deletions could lead to gene fusion products that are tumor-driving. To identify such events we analyzed a series of neuroblastomas by comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) arrays and integrated these data with Affymetrix mRNA profiling data with the bioinformatic tool R2 (http://r2.amc.nl). We identified three neuroblastoma samples with small interstitial deletions at 11q23, upstream of the forkhead-box transcription factor FOXR1. Genes at the proximal side of the deletion were fused to FOXR1, resulting in fusion transcripts of MLL-FOXR1 and PAFAH1B2-FOXR1. FOXR1 expression has only been detected in early embryogenesis. Affymetrix microarray analysis showed high FOXR1 mRNA expression exclusively in the neuroblastomas with micro-deletions and rare cases of other tumor types, including osteosarcoma cell line HOS. RNAi silencing of FOXR1 strongly inhibited proliferation of HOS cells and triggered apoptosis. Expression profiling of these cells and reporter assays suggested that FOXR1 is a negative regulator of forkhead-box factor mediated transcription. The neural crest stem cell line JoMa1 proliferates in culture conditional to activity of a MYC-ER transgene. Over-expression of the wild-type FOXR1 could functionally replace MYC and drive proliferation of JoMa1. We conclude that FOXR1 is recurrently activated in neuroblastoma by intrachromosomal deletion/fusion events, resulting in over-expression of fusion transcripts. Forkhead-box transcription factors have not been previously implicated in neuroblastoma pathogenesis. Furthermore, this is the first identification of intrachromosomal fusion genes in neuroblastoma. Time series Affymetrix U133p2 profiling of Osteosarcoma HOS cells transduced with FOXR1 targeted shRNAs or control shRNA

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Capture of TAD reorganization endows variant patterns of gene transcription (RNA-Seq)

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