C11orf95-RELA reprograms 3D epigenome in supratentorial ependymoma

Jacqueline Jufen Zhu; Nathaniel Jillette; Xiao Nan Li; Albert Wu Cheng; Ching C. Lau

doi:10.1007/s00401-020-02225-8

C11orf95-RELA reprograms 3D epigenome in supratentorial ependymoma

Jacqueline Jufen Zhu, Nathaniel Jillette, Xiao Nan Li, Albert Wu Cheng^*, Ching C. Lau

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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.

Original language	English (US)
Pages (from-to)	951-960
Number of pages	10
Journal	Acta Neuropathologica
Volume	140
Issue number	6
DOIs	https://doi.org/10.1007/s00401-020-02225-8
State	Published - Dec 2020

Keywords

3D genome
C11orf95-RELA
Supratentorial ependymoma
Transcription factor

ASJC Scopus subject areas

Clinical Neurology
Cellular and Molecular Neuroscience
Pathology and Forensic Medicine

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10.1007/s00401-020-02225-8

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title = "C11orf95-RELA reprograms 3D epigenome in supratentorial ependymoma",

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 = "3D genome, C11orf95-RELA, Supratentorial ependymoma, Transcription factor",

author = "Zhu, {Jacqueline Jufen} and Nathaniel Jillette and Li, {Xiao Nan} and Cheng, {Albert Wu} and Lau, {Ching C.}",

note = "Funding Information: We would like to thank members of the CCL laboratory at the Jackson Laboratory for Genomic Medicine for helpful discussions and Amanda Lazarus for administrative support. This work was partially supported by funding from the Chenevert Family Foundation, Inc. (CCL) and the Martin J. Gavin Endowment at Connecticut Children{\textquoteright}s Medical Center (CCL), National Cancer Institute P30CA034196 (to AWC) and the National Human Genome Research Institute R01-HG009900 (to AWC). Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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AU - Jillette, Nathaniel

AU - Li, Xiao Nan

AU - Cheng, Albert Wu

AU - Lau, Ching C.

N1 - Funding Information: We would like to thank members of the CCL laboratory at the Jackson Laboratory for Genomic Medicine for helpful discussions and Amanda Lazarus for administrative support. This work was partially supported by funding from the Chenevert Family Foundation, Inc. (CCL) and the Martin J. Gavin Endowment at Connecticut Children’s Medical Center (CCL), National Cancer Institute P30CA034196 (to AWC) and the National Human Genome Research Institute R01-HG009900 (to AWC). Publisher Copyright: © 2020, The Author(s).

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

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KW - Transcription factor

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C11orf95-RELA reprograms 3D epigenome in supratentorial ependymoma

Abstract

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