C11orf95-RELA reprograms 3D epigenome in supratentorial ependymoma
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ORIGINAL PAPER
C11orf95‑RELA reprograms 3D epigenome in supratentorial ependymoma Jacqueline Jufen Zhu1 · Nathaniel Jillette1 · Xiao‑Nan Li2,3 · Albert Wu Cheng1,4,5,6 · Ching C. Lau1,4,7,8 Received: 18 June 2020 / Revised: 30 July 2020 / Accepted: 2 September 2020 © The Author(s) 2020
Abstract Supratentorial ependymoma (ST-EPN) is a type of malignant brain tumor mainly seen in children. Since 2014, it has been known that an intrachromosomal fusion C11orf95-RELA is an oncogenic driver in ST-EPN [Parker et al. Nature 506:451–455 (2014); Pietsch et al. Acta Neuropathol 127:609–611 (2014)] but the molecular mechanisms of oncogenesis are unclear. Here we show that the C11orf95 component of the fusion protein dictates DNA binding activity while the RELA component is required for driving the expression of ependymoma-associated genes. Epigenomic characterizations using ChIP-seq and HiChIP approaches reveal that C11orf95-RELA modulates chromatin states and mediates chromatin interactions, leading to transcriptional reprogramming in ependymoma cells. Our findings provide important characterization of the molecular underpinning of C11orf95-RELA fusion and shed light on potential therapeutic targets for C11orf95-RELA subtype ependymoma. Keywords C11orf95-RELA · Supratentorial ependymoma · Transcription factor · 3D genome
Introduction Ependymoma is the third most common malignant brain tumor in children. It can be classified into three groups based on location of the tumor: supratentorial, infratentorial and spinal. Currently there is no effective chemotherapy identified and treatment is limited to surgery with or without adjuvant radiation therapy. Because a significant portion of ependymoma is found in young children, radiation therapy is not desirable due to the detrimental effects on the developing brain. Thus, there is an urgent need to develop targeted Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00401-020-02225-8) contains supplementary material, which is available to authorized users.
therapy based on the underlying biology. C11orf95-RELA fusion was found to be the most recurrent structural variation in approximately 70% of supratentorial ependymomas (STEPN) [14, 15]. Neural stem cells transformed by C11orf95RELA were able to form brain tumor in mice [11, 14]. However, how C11orf95-RELA functions in tumorigenesis at the molecular level is largely unknown. We present results here showing that contrary to the hypothesis that C11orf95RELA ependymoma is driven by the RELA component of the fusion, binding affinity of the fusion protein to DNA is dictated by the C11orf95 component. The contribution of the RELA component is to stabilize the DNA binding of the fusion protein and provide its activation domain to drive expression of the target genes.
* Albert Wu Cheng [email protected]
4
The Jackson Laboratory Cancer Center, Bar Harbor, ME, USA
* Ching C. Lau [email protected]
5
Department of Genetics and Genome Sciences, University of Connecticut Health
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