Zc3h13 Regulates Nuclear RNA m6A Methylation and Mouse Embryonic Stem Cell Self-Renewal

Wen, Jing; Lv, Ruitu; Ma, Honghui; Shen, Hongjie; He, Chenxi; Jia-hua, Wang; Jiao, Fangfang; Liu, Huan; Yang, Pengyuan; Tan, Li; Lan, Fei; Shi, Yujiang Geno; He, Chuan; Shi, Yang; Diao, Jiang

doi:10.1016/j.molcel.2018.02.015

Cited by 693 publications

(631 citation statements)

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“…METTL3/PfMT-A70, METTL14/PfMT-A70.2, WTAP/PfWTAP). Co-factors of the human core m 6 A writer complex (left) 49–52 and putative, non-conserved co-factors of P. falciparum (right) are shown in grey.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Transcriptome-wide dynamics of extensive m6A mRNA methylation duringPlasmodium falciparumblood-stage development

Baumgarten

Bryant

Sinha

et al. 2019

Preprint

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39 40 Malaria pathogenesis results from the asexual replication of Plasmodium falciparum 41 within human red blood cells, which relies on a precisely timed cascade of gene 42 expression over a 48-hour life cycle. Although substantial post-transcriptional 43 regulation of this hardwired program has been observed, it remains unclear how 44 these processes are mediated on a transcriptome-wide level. To this end, we 45 identified mRNA modifications in the P. falciparum transcriptome and performed a 46 comprehensive characterization of N 6 -methyladenosine (m 6 A) over the course of 47 blood stage development. Using mass spectrometry and m 6 A RNA sequencing, we 48 demonstrate that m 6 A is highly developmentally regulated, exceeding m 6 A levels 49 known in any other eukaryote. We identify an evolutionarily conserved m 6 A writer 50 complex and show that knockdown of the putative m 6 A methyltransferase by 51 CRISPR interference leads to increased levels of transcripts that normally contain 52 m 6 A. In accordance, we find an inverse correlation between m 6 A status and mRNA 53 stability or translational efficiency. Our data reveal the crucial role of extensive m 6 A 54 mRNA methylation in dynamically fine-tuning the transcriptional program of a 55 unicellular eukaryote as well as a new 'epitranscriptomic' layer of gene regulation in 56 malaria parasites. 57 58 59 Keywords 60 61 Plasmodium falciparum development; mRNA methylation; N 6 -methyladenosine; 62 mRNA degradation; translational efficiency; CRISPR interference 63 64 65 66 Malaria, a mosquito-borne human disease caused by the unicellular apicomplexan 67 parasite Plasmodium falciparum, remains a major global health threat (World Health 68 Organization, 2018). Human pathogenesis results from the 48-hour intra-erythrocytic 69 developmental cycle (IDC), during which each parasite undergoes schizogony within 70 red blood cells (RBC) to create up to 32 new daughter cells (Fig. 1a). Each step of 71 the IDC -RBC invasion (0-hour post infection [hpi]), host cell remodeling, genome 72replication, and eventually RBC egress -is effected by a precisely timed cascade of 73 gene expression. Throughout this process, mRNAs from the majority of genes 74 expressed reach peak abundance only once, which is thought to correspond to the 75 time point when its encoded product is most required 1 . 76At the transcriptional level of gene regulation, silencing is achieved via 77 heterochromatinization of genes encoding variant surface antigens 2 and the inducer 78 of sexual stage development 3 . Heterochromatin, however, is restricted to 79 subtelomeric and several central chromosomal regions 4 , and the large majority of 80 the P. falciparum genome remains in a euchromatic and transcriptionally permissive 81 state throughout the IDC 5 . Recent studies of nucleosome occupancy have shown 82 that dynamic chromatin accessibility in promoter regions strongly correlates with 83 mRNA abundance, and that these sequences can be recognized by transcription 84 factors in vitro 6-8 . Intriguingly, ...

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Section: Resultsmentioning

confidence: 99%

“…In mammalian cells, several adaptor proteins can assemble with and guide the core m 6 A writer complex 49–52 . However, we did not identify orthologs of these cofactors among the proteins that specifically co-immunoprecipitated with PfMT-A70.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome-wide dynamics of extensive m6A mRNA methylation duringPlasmodium falciparumblood-stage development

Baumgarten

Bryant

Sinha

et al. 2019

Preprint

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“…And further studies indicate that VIRMA is engaged in recruiting METTL3‐METTL14‐WTAP at specific site and HAKAI is also an important component of methyltransferase. Besides, ZC3H13 plays a role in anchoring the m 6 A regulatory complex in the nucleus 23. Additionally, Jaffrey et al.…”

Section: The Discovery Of M6a and Its Functionmentioning

confidence: 99%

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

Wang

et al. 2018

J Cellular Molecular Medi

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As the most abundant and reversible RNA modification in eukaryotic cells, m6A triggers a new layer of epi‐transcription. M6A modification occurs through a methylation process modified by “writers” complexes, reversed by “erasers”, and exerts its role depending on various “readers”. Emerging evidence shows that there is a strong association between m6A and human diseases, especially cancers. Herein, we review bi‐aspects of m6A in regulating cancers mediated by the m6A‐associated proteins, which exert vital and specific roles in the development of various cancers. Generally, the m6A modification performs promotion or inhibition functions (dual role) in tumorigenesis and progression of various cancers, which suggests a new concept in cancer regulations. In addition, m6A‐targeted therapies including competitive antagonists of m6A‐associated proteins may provide a new tumour intervention in the future.

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“…Similar to DNA and protein modification, the m 6 A methylation is dynamically and reversibly regulated by methyltransferases ("writers"), binding proteins ("readers"), and demethylases ("erasers") [12]. The RNAs undergo the process of methyl group modification under the action of "writers" that such as METTL3, METTL14, WTAP, RBM15, KIAA1429, and ZC3H13 [13][14][15][16][17][18][19]. Then the "readers" including YTHDF1, YTHDF2, YTHDC1, YTHDC2, HNRNPC recognize those m 6 A-modified RNAs and function in RNA processing, nuclear export, translation and decay [12,17,20].…”

Section: Introductionmentioning

confidence: 99%

Diagnostic, progressive and prognostic performance of m⁶A methylation RNA regulators in lung adenocarcinoma

Zhuang¹,

Chen²,

Mao³

et al. 2020

Int. J. Biol. Sci.

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Background: N6-methyladenosine (m 6 A) RNA methylation is dynamically and reversibly regulated by methyl-transferases ("writers"), binding proteins ("readers"), and demethylases ("erasers"). The m 6 A is restored to adenosine and thus to achieve demethylation modification. The abnormality of m 6 A epigenetic modification in cancer has been increasingly attended. However, we are rarely aware of its diagnostic, progressive and prognostic performance in lung adenocarcinoma (LUAD). Methods and Results: The expression of 13 widely reported m 6 A RNA regulators in LUAD and normal samples were systematically analyzed. There were 12 m 6 A RNA methylation genes displaying aberrant expressions, and an 11-gene diagnostic score model was finally built (Diagnostic score

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Zc3h13 Regulates Nuclear RNA m6A Methylation and Mouse Embryonic Stem Cell Self-Renewal

Cited by 693 publications

References 46 publications

Transcriptome-wide dynamics of extensive m6A mRNA methylation duringPlasmodium falciparumblood-stage development

Transcriptome-wide dynamics of extensive m6A mRNA methylation duringPlasmodium falciparumblood-stage development

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

Diagnostic, progressive and prognostic performance of m⁶A methylation RNA regulators in lung adenocarcinoma

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Zc3h13 Regulates Nuclear RNA m6A Methylation and Mouse Embryonic Stem Cell Self-Renewal

Cited by 693 publications

References 46 publications

Transcriptome-wide dynamics of extensive m6A mRNA methylation duringPlasmodium falciparumblood-stage development

Transcriptome-wide dynamics of extensive m6A mRNA methylation duringPlasmodium falciparumblood-stage development

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

Diagnostic, progressive and prognostic performance of m6A methylation RNA regulators in lung adenocarcinoma

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Product

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Diagnostic, progressive and prognostic performance of m⁶A methylation RNA regulators in lung adenocarcinoma