MYCN drives oncogenesis by cooperating with the histone methyltransferase G9a and the WDR5 adaptor to orchestrate global gene transcription.
MYCN activates canonical MYC targets involved in ribosome biogenesis, protein synthesis, and represses neuronal differentiation genes to drive oncogenesis in neuroblastoma (NB). How MYCN orchestrates global gene expression remains incompletely understood. Our study finds that MYCN binds promoters to...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2024-03-01
|
| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002240&type=printable |
| _version_ | 1797213341501882368 |
|---|---|
| author | Zhihui Liu Xiyuan Zhang Man Xu Jason J Hong Amanda Ciardiello Haiyan Lei Jack F Shern Carol J Thiele |
| author_facet | Zhihui Liu Xiyuan Zhang Man Xu Jason J Hong Amanda Ciardiello Haiyan Lei Jack F Shern Carol J Thiele |
| author_sort | Zhihui Liu |
| collection | DOAJ |
| description | MYCN activates canonical MYC targets involved in ribosome biogenesis, protein synthesis, and represses neuronal differentiation genes to drive oncogenesis in neuroblastoma (NB). How MYCN orchestrates global gene expression remains incompletely understood. Our study finds that MYCN binds promoters to up-regulate canonical MYC targets but binds to both enhancers and promoters to repress differentiation genes. MYCN binding also increases H3K4me3 and H3K27ac on canonical MYC target promoters and decreases H3K27ac on neuronal differentiation gene enhancers and promoters. WDR5 facilitates MYCN promoter binding to activate canonical MYC target genes, whereas MYCN recruits G9a to enhancers to repress neuronal differentiation genes. Targeting both MYCN's active and repressive transcriptional activities using both WDR5 and G9a inhibitors synergistically suppresses NB growth. We demonstrate that MYCN cooperates with WDR5 and G9a to orchestrate global gene transcription. The targeting of both these cofactors is a novel therapeutic strategy to indirectly target the oncogenic activity of MYCN. |
| first_indexed | 2024-04-24T10:56:44Z |
| format | Article |
| id | doaj.art-c1ec3c76324c4ee8b3762bb57f013072 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-04-24T10:56:44Z |
| publishDate | 2024-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-c1ec3c76324c4ee8b3762bb57f0130722024-04-12T05:30:36ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852024-03-01223e300224010.1371/journal.pbio.3002240MYCN drives oncogenesis by cooperating with the histone methyltransferase G9a and the WDR5 adaptor to orchestrate global gene transcription.Zhihui LiuXiyuan ZhangMan XuJason J HongAmanda CiardielloHaiyan LeiJack F ShernCarol J ThieleMYCN activates canonical MYC targets involved in ribosome biogenesis, protein synthesis, and represses neuronal differentiation genes to drive oncogenesis in neuroblastoma (NB). How MYCN orchestrates global gene expression remains incompletely understood. Our study finds that MYCN binds promoters to up-regulate canonical MYC targets but binds to both enhancers and promoters to repress differentiation genes. MYCN binding also increases H3K4me3 and H3K27ac on canonical MYC target promoters and decreases H3K27ac on neuronal differentiation gene enhancers and promoters. WDR5 facilitates MYCN promoter binding to activate canonical MYC target genes, whereas MYCN recruits G9a to enhancers to repress neuronal differentiation genes. Targeting both MYCN's active and repressive transcriptional activities using both WDR5 and G9a inhibitors synergistically suppresses NB growth. We demonstrate that MYCN cooperates with WDR5 and G9a to orchestrate global gene transcription. The targeting of both these cofactors is a novel therapeutic strategy to indirectly target the oncogenic activity of MYCN.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002240&type=printable |
| spellingShingle | Zhihui Liu Xiyuan Zhang Man Xu Jason J Hong Amanda Ciardiello Haiyan Lei Jack F Shern Carol J Thiele MYCN drives oncogenesis by cooperating with the histone methyltransferase G9a and the WDR5 adaptor to orchestrate global gene transcription. PLoS Biology |
| title | MYCN drives oncogenesis by cooperating with the histone methyltransferase G9a and the WDR5 adaptor to orchestrate global gene transcription. |
| title_full | MYCN drives oncogenesis by cooperating with the histone methyltransferase G9a and the WDR5 adaptor to orchestrate global gene transcription. |
| title_fullStr | MYCN drives oncogenesis by cooperating with the histone methyltransferase G9a and the WDR5 adaptor to orchestrate global gene transcription. |
| title_full_unstemmed | MYCN drives oncogenesis by cooperating with the histone methyltransferase G9a and the WDR5 adaptor to orchestrate global gene transcription. |
| title_short | MYCN drives oncogenesis by cooperating with the histone methyltransferase G9a and the WDR5 adaptor to orchestrate global gene transcription. |
| title_sort | mycn drives oncogenesis by cooperating with the histone methyltransferase g9a and the wdr5 adaptor to orchestrate global gene transcription |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002240&type=printable |
| work_keys_str_mv | AT zhihuiliu mycndrivesoncogenesisbycooperatingwiththehistonemethyltransferaseg9aandthewdr5adaptortoorchestrateglobalgenetranscription AT xiyuanzhang mycndrivesoncogenesisbycooperatingwiththehistonemethyltransferaseg9aandthewdr5adaptortoorchestrateglobalgenetranscription AT manxu mycndrivesoncogenesisbycooperatingwiththehistonemethyltransferaseg9aandthewdr5adaptortoorchestrateglobalgenetranscription AT jasonjhong mycndrivesoncogenesisbycooperatingwiththehistonemethyltransferaseg9aandthewdr5adaptortoorchestrateglobalgenetranscription AT amandaciardiello mycndrivesoncogenesisbycooperatingwiththehistonemethyltransferaseg9aandthewdr5adaptortoorchestrateglobalgenetranscription AT haiyanlei mycndrivesoncogenesisbycooperatingwiththehistonemethyltransferaseg9aandthewdr5adaptortoorchestrateglobalgenetranscription AT jackfshern mycndrivesoncogenesisbycooperatingwiththehistonemethyltransferaseg9aandthewdr5adaptortoorchestrateglobalgenetranscription AT caroljthiele mycndrivesoncogenesisbycooperatingwiththehistonemethyltransferaseg9aandthewdr5adaptortoorchestrateglobalgenetranscription |