RBFOX2 recognizes N6-methyladenosine to suppress transcription and block myeloid leukaemia differentiation DOI Creative Commons
Xiaoyang Dou, Yu Xiao, Chao Shen

et al.

Nature Cell Biology, Journal Year: 2023, Volume and Issue: 25(9), P. 1359 - 1368

Published: Aug. 28, 2023

N6-methyladenosine (m6A) methylation can be deposited on chromatin-associated RNAs (caRNAs) by the RNA methyltransferase complex (MTC) to regulate chromatin state and transcription. However, mechanism which MTC is recruited distinct genomic loci remains elusive. Here we identify RBFOX2, a well-studied RNA-binding protein, as factor that preferentially recognizes m6A caRNAs. RBFOX2 recruit RBM15, an component, facilitate of promoter-associated RNAs. RBM15 also physically interacts with YTHDC1 recruits polycomb repressive 2 (PRC2) RBFOX2-bound for silencing transcription suppression. Furthermore, found this RBFOX2/m6A/RBM15/YTHDC1/PRC2 axis plays critical role in myeloid leukaemia. Downregulation notably inhibits survival/proliferation acute leukaemia cells promotes their differentiation. required self-renewal stem/initiation maintenance. Our study presents pathway recruitment deposition caRNAs, resulting locus-selective regulation, has potential therapeutic implications

Language: Английский

Activation of human endogenous retroviruses and its physiological consequences DOI
Nicholas Dopkins, Douglas F. Nixon

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(3), P. 212 - 222

Published: Oct. 23, 2023

Language: Английский

Citations

57
Methylation across the central dogma in health and diseases: new therapeutic strategies DOI Creative Commons
Ruochen Liu, Erhu Zhao,

Huijuan Yu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Aug. 24, 2023

The proper transfer of genetic information from DNA to RNA protein is essential for cell-fate control, development, and health. Methylation DNA, RNAs, histones, non-histone proteins a reversible post-synthesis modification that finetunes gene expression function in diverse physiological processes. Aberrant methylation caused by mutations or environmental stimuli promotes various diseases accelerates aging, necessitating the development therapies correct disease-driver imbalance. In this Review, we summarize operating system across central dogma, which includes writers, erasers, readers, reader-independent outputs. We then discuss how dysregulation contributes neurological disorders, cancer, aging. Current small-molecule compounds target modifiers show modest success certain cancers. methylome-wide action lack specificity lead undesirable biological effects cytotoxicity, limiting their therapeutic application, especially with monogenic cause different directions changes. Emerging tools capable site-specific manipulation hold great promise solve dilemma. With refinement delivery vehicles, these new are well positioned advance basic research clinical translation field.

Language: Английский

Citations

56
Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity DOI
Andrew A. Guirguis, Yaara Ofir-Rosenfeld, Kathy Knezevic

et al.

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(10), P. 2228 - 2247

Published: Aug. 7, 2023

Abstract Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity cancer cells remains a priority. Using novel enzymatic inhibitor RNA methyl­transferase METTL3, we demonstrate global decrease in N6-methyladenosine (m6A) results double-stranded (dsRNA) formation and profound cell-intrinsic interferon response. Through unbiased CRISPR screens, establish dsRNA-sensing signaling are primary mediators potentiate T-cell killing following METTL3 inhibition. We show range immunocompetent mouse models although inhibition is equally efficacious anti–PD-1 therapy, combination has far greater preclinical activity. SPLINTR barcoding, therapy target distinct malignant clones, these therapies overcomes clones insensitive single agents. These data provide mole­cular rationale for employing inhibitors promote clinic. Significance: This work demonstrates stimulates response through dsRNA formation. immunomodulatory mechanism from current immunotherapeutic agents provides molecular with immune-checkpoint blockade augment immunity. article featured Selected Articles Issue, p. 2109

Language: Английский

Citations

54
Stress, epigenetics, and aging: Unraveling the intricate crosstalk DOI Creative Commons
Zeming Wu, Jing Qu, Weiqi Zhang

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 84(1), P. 34 - 54

Published: Nov. 13, 2023

Language: Английский

Citations

54
RBFOX2 recognizes N6-methyladenosine to suppress transcription and block myeloid leukaemia differentiation DOI Creative Commons
Xiaoyang Dou, Yu Xiao, Chao Shen

et al.

Nature Cell Biology, Journal Year: 2023, Volume and Issue: 25(9), P. 1359 - 1368

Published: Aug. 28, 2023

N6-methyladenosine (m6A) methylation can be deposited on chromatin-associated RNAs (caRNAs) by the RNA methyltransferase complex (MTC) to regulate chromatin state and transcription. However, mechanism which MTC is recruited distinct genomic loci remains elusive. Here we identify RBFOX2, a well-studied RNA-binding protein, as factor that preferentially recognizes m6A caRNAs. RBFOX2 recruit RBM15, an component, facilitate of promoter-associated RNAs. RBM15 also physically interacts with YTHDC1 recruits polycomb repressive 2 (PRC2) RBFOX2-bound for silencing transcription suppression. Furthermore, found this RBFOX2/m6A/RBM15/YTHDC1/PRC2 axis plays critical role in myeloid leukaemia. Downregulation notably inhibits survival/proliferation acute leukaemia cells promotes their differentiation. required self-renewal stem/initiation maintenance. Our study presents pathway recruitment deposition caRNAs, resulting locus-selective regulation, has potential therapeutic implications

Language: Английский

Citations

48