Cargando…

BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS

Myc plays a central role in tumorigenesis by orchestrating the expression of genes essential to numerous cellular processes. While it is well established that Myc functions by binding to its target genes to regulate their transcription, the distribution of the transcriptional output across human gen...

Descripción completa

Detalles Bibliográficos
Autores principales: Yang, Rui, Wang, Wenzhe, Dong, Meichen, Roso, Kristen, Bao, Xuhui, Pirozzi, Christopher, Bigner, Darell, Yan, Hai, Ashley, David, Zhabotynsky, Vasyl, Zou, Fei, He, Yiping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168194/
http://dx.doi.org/10.1093/neuonc/noab090.017
_version_ 1783701840358014976
author Yang, Rui
Wang, Wenzhe
Dong, Meichen
Roso, Kristen
Bao, Xuhui
Pirozzi, Christopher
Bigner, Darell
Yan, Hai
Ashley, David
Zhabotynsky, Vasyl
Zou, Fei
He, Yiping
author_facet Yang, Rui
Wang, Wenzhe
Dong, Meichen
Roso, Kristen
Bao, Xuhui
Pirozzi, Christopher
Bigner, Darell
Yan, Hai
Ashley, David
Zhabotynsky, Vasyl
Zou, Fei
He, Yiping
author_sort Yang, Rui
collection PubMed
description Myc plays a central role in tumorigenesis by orchestrating the expression of genes essential to numerous cellular processes. While it is well established that Myc functions by binding to its target genes to regulate their transcription, the distribution of the transcriptional output across human genome in Myc-amplified cancer cells, and the susceptibility of such transcriptional outputs to therapeutic interferences remain to be fully elucidated. Here, we analyze the distribution of transcriptional outputs in Myc-amplified medulloblastoma (MB) cells by profiling nascent total RNAs within a temporal context. This profiling reveals a major portion of transcriptional action in these cells was directed at the genes fundamental to cellular infrastructures, including rRNAs and particularly those in the mitochondrial genome (mtDNA). Notably, even when Myc protein was depleted by as much as 80%, the impact on transcriptional outputs across the genome was limited, with notable reduction mostly in genes of involved in ribosomal biosynthesis, genes residing in mtDNA or encoding mitochondria-localized proteins, and those encoding histones. In contrast to the limited direct impact of Myc depletion, we found that the global transcriptional outputs were highly dependent on the activity of Inosine Monophosphate Dehydrogenases (IMPDHs), rate limiting enzymes for de novo guanine nucleotide synthesis and whose expression in tumor cells was positively correlated with Myc’s expression. Blockage of IMPDHs attenuated the global transcriptional outputs with a particularly strong inhibitory effect on the aforementioned infrastructure genes, which was accompanied by the abrogation of MB cell’s proliferation in vitro and in vivo. Together, our findings reveal a real time action of Myc as a transcriptional factor in tumor cells, gain new insight into the pathogenic mechanism underlying Myc-driven tumorigenesis, and support IMPDHs as a therapeutic vulnerability in MB cells empowered by a high level of Myc oncoprotein.
format Online
Article
Text
id pubmed-8168194
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-81681942021-06-02 BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS Yang, Rui Wang, Wenzhe Dong, Meichen Roso, Kristen Bao, Xuhui Pirozzi, Christopher Bigner, Darell Yan, Hai Ashley, David Zhabotynsky, Vasyl Zou, Fei He, Yiping Neuro Oncol Basic Biology Myc plays a central role in tumorigenesis by orchestrating the expression of genes essential to numerous cellular processes. While it is well established that Myc functions by binding to its target genes to regulate their transcription, the distribution of the transcriptional output across human genome in Myc-amplified cancer cells, and the susceptibility of such transcriptional outputs to therapeutic interferences remain to be fully elucidated. Here, we analyze the distribution of transcriptional outputs in Myc-amplified medulloblastoma (MB) cells by profiling nascent total RNAs within a temporal context. This profiling reveals a major portion of transcriptional action in these cells was directed at the genes fundamental to cellular infrastructures, including rRNAs and particularly those in the mitochondrial genome (mtDNA). Notably, even when Myc protein was depleted by as much as 80%, the impact on transcriptional outputs across the genome was limited, with notable reduction mostly in genes of involved in ribosomal biosynthesis, genes residing in mtDNA or encoding mitochondria-localized proteins, and those encoding histones. In contrast to the limited direct impact of Myc depletion, we found that the global transcriptional outputs were highly dependent on the activity of Inosine Monophosphate Dehydrogenases (IMPDHs), rate limiting enzymes for de novo guanine nucleotide synthesis and whose expression in tumor cells was positively correlated with Myc’s expression. Blockage of IMPDHs attenuated the global transcriptional outputs with a particularly strong inhibitory effect on the aforementioned infrastructure genes, which was accompanied by the abrogation of MB cell’s proliferation in vitro and in vivo. Together, our findings reveal a real time action of Myc as a transcriptional factor in tumor cells, gain new insight into the pathogenic mechanism underlying Myc-driven tumorigenesis, and support IMPDHs as a therapeutic vulnerability in MB cells empowered by a high level of Myc oncoprotein. Oxford University Press 2021-06-01 /pmc/articles/PMC8168194/ http://dx.doi.org/10.1093/neuonc/noab090.017 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. https://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/ (https://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 Basic Biology
Yang, Rui
Wang, Wenzhe
Dong, Meichen
Roso, Kristen
Bao, Xuhui
Pirozzi, Christopher
Bigner, Darell
Yan, Hai
Ashley, David
Zhabotynsky, Vasyl
Zou, Fei
He, Yiping
BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS
title BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS
title_full BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS
title_fullStr BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS
title_full_unstemmed BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS
title_short BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS
title_sort biol-10. distribution and vulnerability of transcriptional outputs across the genome in myc-amplified medulloblastoma cells
topic Basic Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168194/
http://dx.doi.org/10.1093/neuonc/noab090.017
work_keys_str_mv AT yangrui biol10distributionandvulnerabilityoftranscriptionaloutputsacrossthegenomeinmycamplifiedmedulloblastomacells
AT wangwenzhe biol10distributionandvulnerabilityoftranscriptionaloutputsacrossthegenomeinmycamplifiedmedulloblastomacells
AT dongmeichen biol10distributionandvulnerabilityoftranscriptionaloutputsacrossthegenomeinmycamplifiedmedulloblastomacells
AT rosokristen biol10distributionandvulnerabilityoftranscriptionaloutputsacrossthegenomeinmycamplifiedmedulloblastomacells
AT baoxuhui biol10distributionandvulnerabilityoftranscriptionaloutputsacrossthegenomeinmycamplifiedmedulloblastomacells
AT pirozzichristopher biol10distributionandvulnerabilityoftranscriptionaloutputsacrossthegenomeinmycamplifiedmedulloblastomacells
AT bignerdarell biol10distributionandvulnerabilityoftranscriptionaloutputsacrossthegenomeinmycamplifiedmedulloblastomacells
AT yanhai biol10distributionandvulnerabilityoftranscriptionaloutputsacrossthegenomeinmycamplifiedmedulloblastomacells
AT ashleydavid biol10distributionandvulnerabilityoftranscriptionaloutputsacrossthegenomeinmycamplifiedmedulloblastomacells
AT zhabotynskyvasyl biol10distributionandvulnerabilityoftranscriptionaloutputsacrossthegenomeinmycamplifiedmedulloblastomacells
AT zoufei biol10distributionandvulnerabilityoftranscriptionaloutputsacrossthegenomeinmycamplifiedmedulloblastomacells
AT heyiping biol10distributionandvulnerabilityoftranscriptionaloutputsacrossthegenomeinmycamplifiedmedulloblastomacells