N6-Methyladenosine co-transcriptionally directs the demethylation of histone H3K9me2

Li, Yuan; Xia, Ling; Tan, Kaifen; Ye, Xidong; Zuo, Zhixiang; Li, Minchun; Xiao, Rui; Wang, Zihan; Liu, Xiaona; Deng, Mingqiang; Cui, Jinru; Yang, Mengtian; Luo, Qizhi; Sun, Lu; Cao, Xin; Zhu, Haoran; Liu, Tianqi; Hu, Jiaxin; Shi, Junfang; Xiao, Shan; Xia, Laixin

doi:10.1038/s41588-020-0677-3

Cited by 191 publications

(167 citation statements)

References 51 publications

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“…For YTHDC1, recent work has found that RNA interactions with this protein can directly regulate chromatin via recruitment of KDM3B, promoting H3K9me2 demethylation and gene expression (Y. Li et al, 2020).In contrast, this study demonstrates that YTHDC1 can act to regulate chromatin association and transcriptional repression by HOTAIR, although the mechanism by which this is accomplished remains ambiguous. Our data suggest that YTHDC1-mediated transcriptional repression occurs upstream of chromatin modification by PRC2.…”

Section: M6a In Gene Repression and Heterochromatin Formationmentioning

confidence: 64%

A single N6-methyladenosine site in lncRNA HOTAIR regulates its function in breast cancer cells

Porman

Roberts

Chrupcala

et al. 2020

Preprint

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N6-methyladenosine (m6A) is one of the most abundant RNA modifications with important roles in normal and cancer biology, but knowledge of its function on long noncoding RNAs (lncRNAs) remains limited. In this study, we investigate whether m6A plays a role in regulating the function of the HOTAIR lncRNA which contributes to multiple pro-tumor phenotypes in triple-negative breast cancer (TNBC) cells. We identify 14 individual m6A sites within HOTAIR, with a single site (A783) being consistently methylated.Mutation of A783 impairs cellular proliferation and colony formation in TNBC cells. We find that HOTAIR interacts with the nuclear m6A reader YTHDC1 at methylated A783 and additional sites. Interestingly, we determine that modifications at different sites in HOTAIR have differential effects on HOTAIR regulation. Specifically, m6A at A783 regulates HOTAIR localization to chromatin, whereas other m6A sites mediate high HOTAIR levels. We further find that YTHDC1-HOTAIR interactions are required for gene repression, independent of expression level and chromatin recruitment. Altogether, our work suggests a mechanism whereby m6A regulates the function of HOTAIR via mediating the interaction of YTHDC1 with specific m6A sites, promoting chromatin-mediated repression and breast cancer cell aggressiveness.

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Section: M6a In Gene Repression and Heterochromatin Formationmentioning

confidence: 64%

A single N6-methyladenosine site in lncRNA HOTAIR regulates its function in breast cancer cells

Porman

Roberts

Chrupcala

et al. 2020

Preprint

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“…This enzyme then demethylates H3K9me2 and thus removes a repressive histone mark. [ 73 ] This mechanism may be considered as a positive feed‐back loop that helps to maintain transcription. For the carRNAs, which remain chromatin‐associated, the effect of RNA methylation on lifetime may be dominant.…”

Section: Ma In the Dna Of Animals And Plantsmentioning

confidence: 99%

DNA adenine methylation in eukaryotes: Enzymatic mark or a form of DNA damage?

Bochtler

Fernandes

2020

BioEssays

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6‐methyladenine (6mA) is fairly abundant in nuclear DNA of basal fungi, ciliates and green algae. In these organisms, 6mA is maintained near transcription start sites in ApT context by a parental‐strand instruction dependent maintenance methyltransferase and is positively associated with transcription. In animals and plants, 6mA levels are high only in organellar DNA. The 6mA levels in nuclear DNA are very low. They are attributable to nucleotide salvage and the activity of otherwise mitochondrial METTL4, and may be considered as a price that cells pay for adenine methylation in RNA and/or organellar DNA. Cells minimize this price by sanitizing dNTP pools to limit 6mA incorporation, and by converting 6mA that has been incorporated into DNA back to adenine. Hence, 6mA in nuclear DNA should be described as an epigenetic mark only in basal fungi, ciliates and green algae, but not in animals and plants.

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“…m6A modification and other epigenetic regulation, including the interaction of chromatin state, histone modification, and gene expression, are newly emerging fields of m6A modification research. Histone modifications help deliver m6A modifications to actively transcribed nascent RNA [200], and m6A modifications can also remove the methylation of the suppressive H3K9me2 corresponding to the chromatin region and activate gene transcription [207]. In addition, m6A modification can participate in the adjustment of the chromatin state by regulating the stability of chromatin-related regulatory RNAs and affecting the distribution of activated histone modifications (H3K4me3 and H3K27ac) on the chromatin.…”

Section: Discussionmentioning

confidence: 99%

N6-methyladenosine-dependent signalling in cancer progression and insights into cancer therapies

Tan

Zhao

Xiong

et al. 2021

J Exp Clin Cancer Res

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The N6-methyladenosine (m6A) modification is a dynamic and reversible epigenetic modification, which is co-transcriptionally deposited by a methyltransferase complex, removed by a demethylase, and recognized by reader proteins. Mechanistically, m6A modification regulates the expression levels of mRNA and nocoding RNA by modulating the fate of modified RNA molecules, such as RNA splicing, nuclear transport, translation, and stability. Several studies have shown that m6A modification is dysregulated in the progression of multiple diseases, especially human tumors. We emphasized that the dysregulation of m6A modification affects different signal transduction pathways and involves in the biological processes underlying tumor cell proliferation, apoptosis, invasion and migration, and metabolic reprogramming, and discuss the effects on different cancer treatment.

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N6-Methyladenosine co-transcriptionally directs the demethylation of histone H3K9me2

Cited by 191 publications

References 51 publications

A single N6-methyladenosine site in lncRNA HOTAIR regulates its function in breast cancer cells

A single N6-methyladenosine site in lncRNA HOTAIR regulates its function in breast cancer cells

DNA adenine methylation in eukaryotes: Enzymatic mark or a form of DNA damage?

N6-methyladenosine-dependent signalling in cancer progression and insights into cancer therapies

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