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N6-methyladenosine (m6A) is the most abundant chemical modification in mRNA and plays important roles in human and mouse embryonic stem cell pluripotency, maintenance, and differentiation. We have recently reported that m6A is involved in the postnatal control of β-cell function in physiological states and in type 1 and 2 diabetes. However, the precise mechanisms by which m6A acts to regulate the development of human and mouse pancreas are unexplored. Here, we show that the m6A landscape is dynamic during human pancreas development, and that METTL14, one of the m6A writer complex proteins, is essential for the early differentiation of both human and mouse pancreatic cells. Synopsis: Whether N6-methyladenosine (m6A) post-transcriptional modification of mRNA regulates pancreas development and systemic glucose homeostasis remains unclear. This study reports a dynamic m6A landscape during human pancreas development and importance of the m6A writer, METTL14, for early differentiation of both human and mouse pancreatic cells. METTL14 levels increase temporally in developing human pancreatic β-cells. The m6A landscape is dynamic during in vitro human pancreas development. METTL14-mediated m6A modifications regulate genes involved in pancreas and β-cell development. METTL14 is important for development of non-β and ductal cells. The timing of Mettl14 deletion during pancreas development determines phenotype severity in Mettl14 KO mice. The m6A landscape during early differentiation of pancreatic cells is dynamic, and depends on the m6A writer complex component METTL14. [ABSTRACT FROM AUTHOR]

High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing M/CN-amplified neuroblastoma as a model system, we showed that LIN28B expression was associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7-independent enrichment of transcripts encoding components of the translational and ribosomal apparatus and depletion of transcripts of neuronal developmental programs. We further observed that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrated that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a posttranscriptional driver of the metastatic phenotype., Introduction Tight translational control of the transcriptome is a conserved regulatory mechanism during development and the physiological and pathological stress responses (1-3). Activation of ribosomal biogenesis plays a critical role [...]

Background: This study compared neonatal and adult mice-derived Sertoli cells (NSCs and ASCs) to examine the influence of feeder cells derived from donors of different ages on the maintenance of mouse spermatogonial stem cells (SSCs) in vitro. Materials and Methods: SSCs were derived from the testes of six-day-old mice. They were subsequently transferred to Sertoli cells which were isolated by datura stramonium agglutinin (DSA) lectin from neonatal and adult mice for five days. Results: The numbers of spermatogonial colonies, the numbers of cells per colony, and cloning efficiency were assessed in presence of NSCs and ASCs. The expression of α6- and β1-integrin-positive cells was evaluated. Moreover, the functionality of the cells was assessed by their transplantation into the testes of busulfan-induced infertile mice. Colony efficiency assay showed that the number of colonies derived from single spermatogonial cells were significantly higher on NSCs. Additionally, the transplantation of dissociated colonies into the testes of busulfan-induced infertile mice showed their migration to the seminiferous basal membrane. Conclusion: These results show that NSCs may provide a more favorable microenvironment in comparison with ASCs for in vitro culture of spermatogonial colonies. [ABSTRACT FROM AUTHOR]

The emerging "epitranscriptomics" field is providing insights into the biological and pathological roles of different RNA modifications. The RNA methyltransferase METTL1 catalyzes N7-methylguanosine (m 7 G) modification of tRNAs. Here we find METTL1 is frequently amplified and overexpressed in cancers and is associated with poor patient survival. METTL1 depletion causes decreased abundance of m 7 G-modified tRNAs and altered cell cycle and inhibits oncogenicity. Conversely, METTL1 overexpression induces oncogenic cell transformation and cancer. Mechanistically, we find increased abundance of m 7 G-modified tRNAs, in particular Arg-TCT-4-1, and increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon. Accordingly, Arg-TCT expression is elevated in many tumor types and is associated with patient survival, and strikingly, overexpression of this individual tRNA induces oncogenic transformation. Thus, METTL1-mediated tRNA modification drives oncogenic transformation through a remodeling of the mRNA "translatome" to increase expression of growth-promoting proteins and represents a promising anti-cancer target., Competing Interests: Declaration of interests R.I.G. and F.J.S. are co-founders and scientific advisory board members of 28-7 Therapeutics. R.I.G. is a co-founder and scientific advisory board member of Theon Therapeutics. E.Y. is co-funded by STORM Therapeutics., (Copyright © 2021 Elsevier Inc. All rights reserved.)