Cargando…
MBRS-70. FUNCTIONAL DEPENDENCY BETWEEN REST AND DNMT1 IN MEDULLOBLASTOMA
Medulloblastomas exhibit poor neuronal lineage specification. Expression of RE1 Silencing Transcription Factor (REST), a repressor of neurogenesis, is aberrantly elevated in human sonic hedgehog (SHH) medulloblastomas. Constitutive REST expression in mice (REST(TG)) drives medulloblastoma genesis an...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715790/ http://dx.doi.org/10.1093/neuonc/noaa222.574 |
_version_ | 1783619037829267456 |
---|---|
author | Maegawa, Shinji Dobson, Tara Lu, Yue Estecio, Marcos Harmanci, Arif Gopalakrishnan, Vidya |
author_facet | Maegawa, Shinji Dobson, Tara Lu, Yue Estecio, Marcos Harmanci, Arif Gopalakrishnan, Vidya |
author_sort | Maegawa, Shinji |
collection | PubMed |
description | Medulloblastomas exhibit poor neuronal lineage specification. Expression of RE1 Silencing Transcription Factor (REST), a repressor of neurogenesis, is aberrantly elevated in human sonic hedgehog (SHH) medulloblastomas. Constitutive REST expression in mice (REST(TG)) drives medulloblastoma genesis and promotes tumor progression in the context of Ptch1 haploinsufficiency (Ptch(+/−)), implicating it as a driver of tumorigenesis. Tumor formation in Ptch(+/−)/REST(TG) mice showed significantly decreased latency and increased penetrance compared to that in Ptch(+/−) mice. Since REST silences gene expression by chromatin remodeling, we sought to identify cooperating epigenetic events that contributed to its oncogenic activity. To this end, we performed a loss of function screen employing a bar-coded library of short hairpin RNAs against epigenes, to identify candidates whose loss could create a proliferative vulnerability in the context of REST-elevation. This screen identified DNA methyltransferase 1 (DNMT1) as a high-priority epigenetic modifier. DNMT1 and the Ubiquitin like with PHD and Ring finger domain 1 (UHRF1) proteins are essential for methylation of hemi-methylated DNA at the replication fork during S-phase. Their expression is downregulated during neuronal differentiation. In human SHH-medulloblastoma tumors, REST and UHRF1 expression are positively correlated with higher levels of both genes noted specifically in the SHH-beta subtype, and is associated with poor prognosis. The requirement for DNMT1/UHRF1 in the context of REST elevation, was established by RNA-Seq and Reduced Representation Bisulfite Sequencing (RRBS), which revealed hypermethylation and downregulated expression of REST-target genes needed for neurogenesis. Thus, DNMT1/UHRF1 is a functional and potential therapeutic vulnerability in REST-elevated SHH medulloblastomas. |
format | Online Article Text |
id | pubmed-7715790 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-77157902020-12-09 MBRS-70. FUNCTIONAL DEPENDENCY BETWEEN REST AND DNMT1 IN MEDULLOBLASTOMA Maegawa, Shinji Dobson, Tara Lu, Yue Estecio, Marcos Harmanci, Arif Gopalakrishnan, Vidya Neuro Oncol Medulloblastoma (Research) Medulloblastomas exhibit poor neuronal lineage specification. Expression of RE1 Silencing Transcription Factor (REST), a repressor of neurogenesis, is aberrantly elevated in human sonic hedgehog (SHH) medulloblastomas. Constitutive REST expression in mice (REST(TG)) drives medulloblastoma genesis and promotes tumor progression in the context of Ptch1 haploinsufficiency (Ptch(+/−)), implicating it as a driver of tumorigenesis. Tumor formation in Ptch(+/−)/REST(TG) mice showed significantly decreased latency and increased penetrance compared to that in Ptch(+/−) mice. Since REST silences gene expression by chromatin remodeling, we sought to identify cooperating epigenetic events that contributed to its oncogenic activity. To this end, we performed a loss of function screen employing a bar-coded library of short hairpin RNAs against epigenes, to identify candidates whose loss could create a proliferative vulnerability in the context of REST-elevation. This screen identified DNA methyltransferase 1 (DNMT1) as a high-priority epigenetic modifier. DNMT1 and the Ubiquitin like with PHD and Ring finger domain 1 (UHRF1) proteins are essential for methylation of hemi-methylated DNA at the replication fork during S-phase. Their expression is downregulated during neuronal differentiation. In human SHH-medulloblastoma tumors, REST and UHRF1 expression are positively correlated with higher levels of both genes noted specifically in the SHH-beta subtype, and is associated with poor prognosis. The requirement for DNMT1/UHRF1 in the context of REST elevation, was established by RNA-Seq and Reduced Representation Bisulfite Sequencing (RRBS), which revealed hypermethylation and downregulated expression of REST-target genes needed for neurogenesis. Thus, DNMT1/UHRF1 is a functional and potential therapeutic vulnerability in REST-elevated SHH medulloblastomas. Oxford University Press 2020-12-04 /pmc/articles/PMC7715790/ http://dx.doi.org/10.1093/neuonc/noaa222.574 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Medulloblastoma (Research) Maegawa, Shinji Dobson, Tara Lu, Yue Estecio, Marcos Harmanci, Arif Gopalakrishnan, Vidya MBRS-70. FUNCTIONAL DEPENDENCY BETWEEN REST AND DNMT1 IN MEDULLOBLASTOMA |
title | MBRS-70. FUNCTIONAL DEPENDENCY BETWEEN REST AND DNMT1 IN MEDULLOBLASTOMA |
title_full | MBRS-70. FUNCTIONAL DEPENDENCY BETWEEN REST AND DNMT1 IN MEDULLOBLASTOMA |
title_fullStr | MBRS-70. FUNCTIONAL DEPENDENCY BETWEEN REST AND DNMT1 IN MEDULLOBLASTOMA |
title_full_unstemmed | MBRS-70. FUNCTIONAL DEPENDENCY BETWEEN REST AND DNMT1 IN MEDULLOBLASTOMA |
title_short | MBRS-70. FUNCTIONAL DEPENDENCY BETWEEN REST AND DNMT1 IN MEDULLOBLASTOMA |
title_sort | mbrs-70. functional dependency between rest and dnmt1 in medulloblastoma |
topic | Medulloblastoma (Research) |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715790/ http://dx.doi.org/10.1093/neuonc/noaa222.574 |
work_keys_str_mv | AT maegawashinji mbrs70functionaldependencybetweenrestanddnmt1inmedulloblastoma AT dobsontara mbrs70functionaldependencybetweenrestanddnmt1inmedulloblastoma AT luyue mbrs70functionaldependencybetweenrestanddnmt1inmedulloblastoma AT esteciomarcos mbrs70functionaldependencybetweenrestanddnmt1inmedulloblastoma AT harmanciarif mbrs70functionaldependencybetweenrestanddnmt1inmedulloblastoma AT gopalakrishnanvidya mbrs70functionaldependencybetweenrestanddnmt1inmedulloblastoma |