Small-molecule inhibition of the METTL3/METTL14 complex suppresses neuroblastoma tumor growth and promotes differentiation.

The N6-methyladenosine (m6A) RNA modification is an important regulator of gene expression. m6A is deposited by a methyltransferase complex that includes methyltransferase-like 3 (METTL3) and methyltransferase-like 14 (METTL14). High levels of METTL3/METTL14 drive the growth of many types of adult cancer, and METTL3/METTL14 inhibitors are emerging as new anticancer agents. However, little is known about the m6A epitranscriptome or the role of the METTL3/METTL14 complex in neuroblastoma, a common pediatric cancer. Here, we show that METTL3 knockdown or pharmacologic inhibition with the small molecule STM2457 leads to reduced neuroblastoma cell proliferation and increased differentiation. These changes in neuroblastoma phenotype are associated with decreased m6A deposition on transcripts involved in nervous system development and neuronal differentiation, with increased stability of target mRNAs. In preclinical studies, STM2457 treatment suppresses the growth of neuroblastoma tumors in vivo. Together, these results support the potential of METTL3/METTL14 complex inhibition as a therapeutic strategy against neuroblastoma.

Mandibular Body Osteotomy Combined with Sagittal Split Ramus Osteotomy for the Treatment of Severe Skeletal Class â ¢ Malocclusion with Ankylosed Teeth.

This study presents a combination of 2 different surgery procedures performed on the mandible as part of the treatment aiming to improve the facial profile and occlusal function of patients with severe skeletal class Ⅲ malocclusion and bilateral edentulous gaps. The teeth next to the edentulous gaps were found to be ankylosed. Mandibular setback by bilateral sagittal split ramus osteotomies and mandibular body osteotomies, combined with Le Fort Ⅰ level maxillary advancement were performed, since the chief complaint of the patient was a concave profile. As a result, the skeletal class Ⅲ malocclusion had been corrected, a satisfying facial profile had been achieved, and no apparent adverse effect was found. Thus, it has been proved that the combination of sagittal split ramus osteotomy and mandibular body osteotomy is available for correcting skeletal class Ⅲ malocclusion.

Sequencing of N6-methyl-deoxyadenosine at single-base resolution across the mammalian genome.

Although DNA N6-methyl-deoxyadenosine (6mA) is abundant in bacteria and protists, its presence and function in mammalian genomes have been less clear. We present Direct-Read 6mA sequencing (DR-6mA-seq), an antibody-independent method, to measure 6mA at base resolution. DR-6mA-seq employs a unique mutation-based strategy to reveal 6mA sites as misincorporation signatures without any chemical or enzymatic modulation of 6mA. We validated DR-6mA-seq through the successful mapping of the well-characterized G(6mA)TC motif in the E. coli DNA. As expected, when applying DR-6mA-seq to mammalian systems, we found that genomic DNA (gDNA) 6mA abundance is generally low in most mammalian tissues and cells; however, we did observe distinct gDNA 6mA sites in mouse testis and glioblastoma cells. DR-6mA-seq provides an enabling tool to detect 6mA at single-base resolution for a comprehensive understanding of DNA 6mA in eukaryotes.