RNA m6A regulates transcription via DNA demethylation and chromatin accessibility

Deng, Shuang; Zhang, Jialiang; Su, Jiachun; Zuo, Zhixiang; Zeng, Lingxing; Liu, Kaijing; Zheng, Yanfen; Huang, Xudong; Bai, Ruihong; Zhuang, Lisha; Ye, Ying; Li, Mei; Pan, Ling; Deng, Junge; Wu, Guandi; Li, Rui; Zhang, Shaoping; Wu, Chen; Lin, Dongxin; Chen, Jianjun; Zheng, Jian

doi:10.1038/s41588-022-01173-1

Cited by 86 publications

(50 citation statements)

References 73 publications

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“…The newest study found that the RNA m 6 A level in esophageal squamous cell carcinoma tissues is significantly higher than that in paracarcinomic tissue. Further studies have shown that RNA m 6 A can negatively regulate the DNA methylation of esophageal cancer through FMR1 Autosomal Homolog 1 (FXR1) and TET1 and play an important role in the development of cancer [130]. However, other types of caRNAs such as some cir-cRNAs, snRNAs, snoRNAs and carRNAs seem to rarely associate with m 6 A modification in cancer.…”

Section: Emerging Roles Of Carnas Related With M 6 a Modification In ...mentioning

confidence: 99%

The chromatin-associated RNAs in gene regulation and cancer

et al. 2023

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Eukaryotic genomes are prevalently transcribed into many types of RNAs that translate into proteins or execute gene regulatory functions. Many RNAs associate with chromatin directly or indirectly and are called chromatin-associated RNAs (caRNAs). To date, caRNAs have been found to be involved in gene and transcriptional regulation through multiple mechanisms and have important roles in different types of cancers. In this review, we first present different categories of caRNAs and the modes of interaction between caRNAs and chromatin. We then detail the mechanisms of chromatin-associated nascent RNAs, chromatin-associated noncoding RNAs and emerging m6A on caRNAs in transcription and gene regulation. Finally, we discuss the roles of caRNAs in cancer as well as epigenetic and epitranscriptomic mechanisms contributing to cancer, which could provide insights into the relationship between different caRNAs and cancer, as well as tumor treatment and intervention.

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Section: Emerging Roles Of Carnas Related With M 6 a Modification In ...mentioning

confidence: 99%

The chromatin-associated RNAs in gene regulation and cancer

et al. 2023

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“…A multiomics approach identifies genes potentially regulated through m 6 A RNA methylation has been implicated in various aspects of the RNA life cycle in the cell 42 , from RNA processing 43 to RNA stability 44 to translation 45,46 , and more recently, crosstalk between epitranscriptome and epigenome [47][48][49][50] . To further understand the connection between global DNA hypomethylation and RNA dynamics in AML cells, we set out to interrogate, via an integrated multiomics approach, the effects of decitabine-induced RNA hypermethylation on AML cells.…”

Section: Dnmt1 Inhibition In Aml Cells Results In Hypermethylation Of...mentioning

confidence: 99%

A multiomics approach reveals RNA dynamics promote cellular sensitivity to DNA hypomethylation

Arab

Dai

et al. 2022

Preprint

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The search for new approaches in cancer therapy requires a mechanistic understanding of cancer vulnerabilities and anti-cancer drug mechanisms of action. Problematically, some effective therapeutics target cancer vulnerabilities that we do not understand and have poorly defined mechanisms of anti-cancer activity. One such drug is decitabine, which is a frontline therapeutic approved for the treatment of high-risk acute myeloid leukemia (AML). Decitabine is thought to kill cancer cells selectively via inhibition of DNA methyltransferase enzymes, but the genes and mechanisms involved remain unclear. Here, we apply an integrated multiomics and CRISPR functional genomics approach to identify genes and processes associated with response to decitabine in AML cells. Our integrated multiomics approach reveals RNA dynamics are key regulators of DNA hypomethylation induced cell death. Specifically, regulation of RNA decapping, splicing and RNA methylation emerge as critical regulators of decitabine killing. Our results provide insights into the mechanisms of decitabine anti-cancer activity in treatment of AML and identify combination therapies which could potentiate decitabine anti-cancer activity.

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“…It is plausible that crosstalk between RNA-m 6 A and DNA-5hmC is also regulating macrophage biology. Notably, recent work has shown that RNA-m 6 A regulates TET-1-mediated DNA 5-hydroxymethylation to promote transcription and chromatin accessibility in cancer (99). Future work should aim to distinguish the importance of the RNA-m 6 A-RNA-5hmC axis and the RNA-m 6 A-DNA-5hmC axis to gene expression regulation in macrophage development and functions.…”

Section: Discussionmentioning

confidence: 99%

RNA m⁶A and 5hmC regulate monocyte and macrophage gene expression programs

Pinello

Song

Lee

et al. 2022

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Background: RNA modifications are essential for the establishment of cellular identity. Although increasing evidence indicates that RNA modifications regulate the innate immune response, their role in monocyte-to-macrophage differentiation and polarisation is unclear. To date, most studies have focused on m6A, while other RNA modifications, including 5hmC, remain poorly characterised. The interplay between different RNA modifications that may occur in specific cellular contexts remains similarly unexplored. Results: We profiled m6A and 5hmC epitranscriptomes, transcriptomes, translatomes and proteomes of monocytes and macrophages at rest and pro- and anti-inflammatory states. We observed that decreased expression of m6A and 5hmC writers, METTL3 and TET-enzymes respectively, facilitated monocyte-to-macrophage differentiation. Despite a global trend of m6A and 5hmC loss during macrophage differentiation, enrichment of m6A and/or 5hmC on specific categories of transcripts essential for macrophage differentiation positively correlated with their expression and translation. m6A and 5hmC mark and are associated with the expression of transcripts with critical functions in pro- and anti-inflammatory macrophages. Notably, we also discovered the coexistence of m6A and 5hmC marking alternatively-spliced isoforms and/or opposing ends of the untranslated regions (UTR) of transcripts with key roles in macrophage biology. In specific examples, RNA 5hmC controls the decay of transcripts independently of m6A. Conclusions: This study: i) uncovers m6A, 5hmC and their writer enzymes as regulators of monocyte and macrophage gene expression programs and ii) provides a comprehensive dataset to interrogate the role of RNA modifications in a plastic system. Altogether, this work sheds light on the role of RNA modifications as central regulators of effector cells in innate immunity.

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RNA m6A regulates transcription via DNA demethylation and chromatin accessibility

Cited by 86 publications

References 73 publications

The chromatin-associated RNAs in gene regulation and cancer

The chromatin-associated RNAs in gene regulation and cancer

A multiomics approach reveals RNA dynamics promote cellular sensitivity to DNA hypomethylation

RNA m⁶A and 5hmC regulate monocyte and macrophage gene expression programs

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RNA m6A regulates transcription via DNA demethylation and chromatin accessibility

Cited by 86 publications

References 73 publications

The chromatin-associated RNAs in gene regulation and cancer

The chromatin-associated RNAs in gene regulation and cancer

A multiomics approach reveals RNA dynamics promote cellular sensitivity to DNA hypomethylation

RNA m6A and 5hmC regulate monocyte and macrophage gene expression programs

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RNA m⁶A and 5hmC regulate monocyte and macrophage gene expression programs