METTL14 is a chromatin regulator independent of its RNA N6-methyladenosine methyltransferase activity

METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m6A methyltransferase complex (MTC) that installs m6A. Surprisingly, depletion of METTL3 or METTL14 displayed distinct effects on stemness maintenance of mouse embryonic stem cell (mESC). While comparable global hypo-methylation in RNA m6A was observed in Mettl3 or Mettl14 knockout mESCs, respectively. Mettl14 knockout led to a globally decreased nascent RNA synthesis, whereas Mettl3 depletion resulted in transcription upregulation, suggesting that METTL14 might possess an m6A-independent role in gene regulation. We found that METTL14 colocalizes with the repressive H3K27me3 modification. Mechanistically, METTL14, but not METTL3, binds H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3. Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression. The effects of METTL14 on regulation of H3K27me3 is essential for the transition from self-renewal to differentiation of mESCs. This work reveals a regulatory mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m6A, and critically impacts transcriptional regulation, stemness maintenance, and differentiation of mESCs.

Minimally invasive plate osteosynthesis and humeral head replacement for treatment of elderly patients with Neer four-part fractures / 中华创伤杂志

ObjectiveTo identify the curative effect of minimally invasive plate osteosynthesis (MIPO) and humeral head replacement in treatment of elderly patients with Neer four-part fractures.MethodsUsing the deltoid pectoral approach,28 patients with fresh Neer four-part fractures were treated by the locking plate combined with MIPO (Group A) and 27 by the humeral head replacement (Group B).Neer score,Constant-Murley score and simple shoulder test (SST) questionnaire were adopted for assessing the treatment outcome.ResultsGroup A was followed up for mean 32.1 months,which showed screws protruding into the joint space in two patients,tuberosity upward and backward displacement in one and femoral head ischemic necrosis in one.The mean visual analog scale (VAS) score,the mean Neer score and the mean Constant-Murley score were 2.2 points,88.6 points and 86.5 points respectively.There were average 9.0 answers for “yes” in the SST questionnaire.Group B were followed up for mean 34.6 months,which showed shoulder dislocation or subluxation in four patients,tuberosity displacement or excessive reduction in eight.The mean VAS score,the mean Neer score and the mean Constant-Murley score were 2.4 points,78.9 points and 77.3 points respectively.The mean number of answer for “yes” in SST questionnaire was 8.0 questions.There showed no statistical difference in VAS score between the two groups.While statistical difference was found in complications,Neer score,Constant-Murley score and SST score between two groups,with Group A superior to Group B.Conclusions For most elderly patients with Neer four-part fractures,MIPO has satisfactory results under strict control of surgical indications and technical tips.The humeral head replacement surgery still has many unresolved problems and needs careful consideration.