The RNA N6-methyladenosine modification landscape of human fetal tissues

Xiao, Shan; Cao, Shuo; Huang, Quan; Xia, Ling; Deng, Mingqiang; Yang, Mengtian; Jia, Guiru; Liu, Xiaona; Shi, Junfang; Wang, Weishi; Li, Yuan; Lee, Sun; Zhu, Haoran; Tan, Kaifen; Luo, Qizhi; Zhong, Ming; He, Chunjiang; Xia, Laixin

doi:10.1038/s41556-019-0315-4

Cited by 143 publications

(149 citation statements)

References 66 publications

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“…We also highlight the specificity of both m 6 A and m 6 Am in brain tissues and show the brain-specific m 6 A are enriched in brain-related function, further supporting that m 6 A could play unique roles for brain tissues. It’s worth mentioning that during the preparation of this manuscript, m 6 A methylome in human fetus tissues was reported (Xiao et al, 2019). Although different human tissue samples were used, it appears that m 6 A methylome in brain tissues of fetus is also highly specific.…”

Section: Discussionmentioning

confidence: 96%

Landscape and regulation of m⁶A and m⁶Am methylome across human and mouse tissues

Liu

Cai

et al. 2019

Preprint

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23 24 2 SUMMARY 1 N 6 -methyladenosine (m 6 A), the most abundant internal mRNA modification, 2 and N 6 ,2'-O-dimethyladenosine (m 6 Am), found at the first-transcribed 3 nucleotide, are two examples of dynamic and reversible epitranscriptomic 4 marks. However, the profiles and distribution patterns of m 6 A and m 6 Am 5 across different human and mouse tissues are poorly characterized. Here we 6 report the m 6 A and m 6 Am methylome through an extensive profiling of 42 7 human tissues and 16 mouse tissue samples. Globally, the m 6 A and m 6 Am 8peaks in non-brain tissues demonstrates mild tissue-specificity but are 9 correlated in general, whereas the m 6 A and m 6 Am methylomes of brain tissues 10 are clearly resolved from the non-brain tissues. Nevertheless, we identified a 11 small subset of tissue-specific m 6 A peaks that can readily classify the tissue 12 types. The number of m 6 A and m 6 Am peaks are partially correlated with the 13 expression levels of their writers and erasers. In addition, the m 6 A-and 14 m 6 Am-containing regions are enriched for single nucleotide polymorphisms. 15Furthermore, cross-species analysis of m 6 A and m 6 Am methylomes revealed 16 that species, rather than tissue types, is the primary determinant of methylation. 17Collectively, our study provides an in-depth resource for dissecting the 18 landscape and regulation of the m 6 A and m 6 Am epitranscriptomic marks 19 across mammalian tissues. 20 21

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Section: Discussionmentioning

confidence: 96%

Landscape and regulation of m⁶A and m⁶Am methylome across human and mouse tissues

Liu

Cai

et al. 2019

Preprint

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“…With rare exceptions (e.g. that showed high overlap and little clustering by tissue type (Figure 2c) (55). This suggests that although 188 there is evidence that m 6 A levels vary by tissue (19), modified sites are consistent.…”

Section: Conclusion (Additional File 3) 126mentioning

confidence: 93%

Limits in the detection of m⁶A changes using MeRIP/m⁶A-seq

McIntyre

Gokhale

Cerchietti

et al. 2019

Preprint

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AbstractMany cellular mRNAs contain the modified base m6A, and recent studies have suggested that various stimuli can lead to changes in m6A. The most common method to map m6A and to predict changes in m6A between conditions is methylated RNA immunoprecipitation sequencing (MeRIP-seq), through which methylated regions are detected as peaks in transcript coverage from immunoprecipitated RNA relative to input RNA. Here, we generated replicate controls and reanalyzed published MeRIP-seq data to estimate reproducibility across experiments. We found that m6A peak overlap in mRNAs varies from ∼30 to 60% between studies, even in the same cell type. We then assessed statistical methods to detect changes in m6A peaks as distinct from changes in gene expression. However, from these published data sets, we detected few changes under most conditions and were unable to detect consistent changes across studies of similar stimuli. Overall, our work identifies limits to MeRIP-seq reproducibility in the detection both of peaks and of peak changes and proposes improved approaches for analysis of peak changes.

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“…Post-transcriptional modifications have also been observed, such as cytosine methylation by NSun7, which may promote stability of eRNAs (Aguilo et al, 2016). Another study found enrichment of N 6 -methyladenosine (m 6 A) among enhancer-derived long intergenic non-coding RNAs (e-lincRNAs), which plays roles in RNA structure, stability, and processing (Xiao et al, 2019). Thus, the true diversity of eRNAs is not captured in its lengths or directionality of transcription, but in the various biological functions its secondary structures and post-transcriptional modifications portend.…”

Section: Structure and Heterogeneity Of Ernamentioning

confidence: 99%

“…The m 6 A marks serve as binding platforms for YTHDF proteins and arranges their IDRs to induce phase separation (Ries et al, 2019). Interestingly, this same m 6 A modification is enriched in eRNA (Xiao et al, 2019). eRNA is known to interact with proteins such as Med1 and BRD4, the IDRs of which contribute to super enhancer formation through phase separation .…”

Section: Enhancers Erna and Phase Separationmentioning

confidence: 99%

Diversity and Emerging Roles of Enhancer RNA in Regulation of Gene Expression and Cell Fate

Arnold

Wells

2020

Front. Cell Dev. Biol.

178

157

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Enhancers are cis-regulatory elements in the genome that cooperate with promoters to control target gene transcription. Unlike promoters, enhancers are not necessarily adjacent to target genes and can exert their functions regardless of enhancer orientations, positions and spatial segregations from target genes. Thus, for a long time, the question as to how enhancers act in a temporal and spatial manner attracted considerable attention. The recent discovery that enhancers are also abundantly transcribed raises interesting questions about the exact roles of enhancer RNA (eRNA) in gene regulation. In this review, we highlight the process of enhancer transcription and the diverse features of eRNA. We review eRNA functions, which include enhancer-promoter looping, chromatin modifying, and transcription regulating. As eRNA are transcribed from active enhancers, they exhibit tissue and lineage specificity, and serve as markers of cell state and function. Finally, we discuss the unique relationship between eRNA and super enhancers in phase separation wherein eRNA may contribute significantly to cell fate decisions.

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The RNA N6-methyladenosine modification landscape of human fetal tissues

Cited by 143 publications

References 66 publications

Landscape and regulation of m⁶A and m⁶Am methylome across human and mouse tissues

Landscape and regulation of m⁶A and m⁶Am methylome across human and mouse tissues

Limits in the detection of m⁶A changes using MeRIP/m⁶A-seq

Diversity and Emerging Roles of Enhancer RNA in Regulation of Gene Expression and Cell Fate

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The RNA N6-methyladenosine modification landscape of human fetal tissues

Cited by 143 publications

References 66 publications

Landscape and regulation of m6A and m6Am methylome across human and mouse tissues

Landscape and regulation of m6A and m6Am methylome across human and mouse tissues

Limits in the detection of m6A changes using MeRIP/m6A-seq

Diversity and Emerging Roles of Enhancer RNA in Regulation of Gene Expression and Cell Fate

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Product

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Landscape and regulation of m⁶A and m⁶Am methylome across human and mouse tissues

Landscape and regulation of m⁶A and m⁶Am methylome across human and mouse tissues

Limits in the detection of m⁶A changes using MeRIP/m⁶A-seq