METTL3-mediated m^(6)A RNA methylation regulates dorsal lingual epithelium homeostasis

The dorsal lingual epithelium,which is composed of taste buds and keratinocytes differentiated from K14^(+)basal cells,discriminates taste compounds and maintains the epithelial barrier.N6-methyladenosine(m^(6)A)is the most abundant mRNA modification in eukaryotic cells.How METTL3-mediated m^(6)A modification regulates K14^(+)basal cell fate during dorsal lingual epithelium formation and regeneration remains unclear.Here we show knockout of Mettl3 in K14^(+)cells reduced the taste buds and enhanced keratinocytes.Deletion of Mettl3 led to increased basal cell proliferation and decreased cell division in taste buds.Conditional Mettl3 knock-in mice showed little impact on taste buds or keratinization,but displayed increased proliferation of cells around taste buds in a protective manner during post-irradiation recovery.Mechanically,we revealed that the most frequent m^(6)A modifications were enriched in Hippo and Wnt signaling,and specific peaks were observed near the stop codons of Lats1 and FZD7.Our study elucidates that METTL3 is essential for taste bud formation and could promote the quantity recovery of taste bud after radiation.

Prognostic Evaluation for Oral Squamous Cell Carcinoma:A Novel Method Based on m6A Methylation Regulators

Objective:This study aimed to examine a novel method for prognostic evaluation of patients with oral squamous cell carcinoma(OSCC)based on the expression of heterogeneous nuclear ribonucleoprotein C(HNRNPC),YTH domain-binding protein 2(YTHDF2),and methyltransferase 14(METTL14).Methods:We obtained the RNA sequence and clinical information of OSCC patients from The Cancer Genome Atlas database.An optical method was established by the least absolute shrinkage and selection operator Cox regression algorithm,which was used to calculate the risk score of every sample.In addition,all samples(n=239)were classified into high-risk(n=119)and low-risk(n=120)groups,and the overall survival(OS)time and clinical characteristics were compared between groups.Moreover,bioinformatics analysis was carried out.Gene set enrichment analysis was performed to investigate the signaling pathways of HNRNPC,YTHDF2,and METTL14.Results:The two groups showed significantly different OS time,tumor grades,tumor stages,and pathologic T stages(P<0.05).The receiver operating characteristic analysis identified that our method was effective and it was more accurate than use of age,gender,tumor grade,tumor stage,pathologic T stage,and pathologic N stage in OSCC prognostic prediction.Gene set enrichment analysis revealed that HNRNPC,YTHDF2,and METTL14 were mainly associated with ubiquitin-mediated proteolysis,cell cycle,RNA degradation,and spliceosome signaling pathways.Conclusion:The method based on the expression of HNRNPC,YTHDF2,and METTL14 can predict the prognosis of patients with OSCC independently,and its prognostic value is better than that of clinicopathological characteristic indicators.

Coordinated transcription of ANRIL and P16 genes is silenced by P16 DNA methylation

Objective： To investigate the relationship between the transcription of ANRIL, P15, P14 and P16 at the same locus and the regulation mechanism of ANRIL.Methods： Publicly available database of Cancer Cell Line Encyclopedia（CCLE） was used in bioinformatic analyses. Methylation of Cp G islands was detected by denaturing high performance liquid chromatography（DHPLC）. Gene transcript levels were determined using quantitative real-time polymerase chain reaction（q RTPCR） assays. An engineered P16-specific transcription factor and DNA methyltransferase were used to induce P16-specific DNA demethylation and methylation.Results： The expression level of ANRIL was positively and significantly correlated with that of P16 but not with that of P15 in the CCLE database. This was confirmed in human cell lines and patient colon tissue samples. In addition, ANRIL was significantly upregulated in colon cancer tissues. Transcription of ANRIL and P16 was observed only in cell lines in which the P16 alleles were unmethylated and not in cell lines with fully methylated P16 alleles.Notably, P16-specific methylation significantly decreased transcription of P16 and ANRIL in BGC823 and GES1 cells. In contrast, P16-specific demethylation re-activated transcription of ANRIL and P16 in H1299 cells（P〈0.001）.Alteration of ANRIL expression was not induced by P16 expression changes.Conclusions： ANRIL and P16 are coordinately transcribed in human cells and regulated by the methylation status of the P16 Cp G islands around the transcription start site.

RNA methylation regulates hematopoietic stem and progenitor cell development

Methylation of adenosine base on the nitrogen-6 position （N6-methyladenosine, m^6A） is the most common and abundant modification on mRNA transcripts. This post-transcriptional modification was first described in the 1970s in hepatoma cells （Desrosiers et al., 1974）.

New Edges of RNA Adenosine Methylation Modifications

Recently an article published in Molecular Cell reveals the mechanism of a nuclear N6-methyladenosine（m^6A）reader,the YTH domain-containing protein 1（YTHDC1）,in regulating pre-m RNA splicing[1].Meanwhile,two additional articles published in Nature and Nature Chemical Biology report the