Role of epigenetic m⁶A RNA methylation in vascular development:mettl3regulates vascular development through PHLPP2/mTOR‐AKT signaling

Abstract

N 6 -methyladenosine (m6A) methylation is the most prevalent RNA modification, and it emerges as an important regulatory mechanism of gene expression involved in many cellular and biological processes. However, the role of m 6 A methylation in vascular development is not clear. The m 6 A RNA methylation is regulated by dynamic interplay among methyltransferases, binding proteins, and demethylases.Mettl3 is a member of the mettl3-mettl14 methyltransferase complex, referred to as writers that catalyze m6A RNA methylation. Here, we used CRISPR-Cas9 genome editing to develop two lines of knockout (KO) zebrafish for mettl3. Heterozygous mettl3 +/− KO embryos show defective vascular development, which is directly visible in fli-EGFP and flk-EGFP zebrafish. Alkaline phosphatase staining and whole mount in situ hybridization with cdh5, and flk markers demonstrated defective development of intersegmental vessels (ISVs), subintestinal vessels (SIVs), interconnecting vessels (ICVs) and dorsal longitudinal anastomotic vessels (DLAV) in both heterozygous mettl3 +/− and homozygous mettl3 −/− KO zebrafish embryos. Similar phenotypes were observed in zebrafish embryos with morpholino knockdown (KD) of mettl3; however, the vascular defects were rescued fully by overexpression of constitutively active AKT1. KD of METTL3 in human endothelial cells inhibited cell 2 of 15 | PARIAL et AL.

METTL14 promotes apoptosis of spinal cord neurons by inducing EEF1A2 m6A methylation in spinal cord injury

“…The Akt/mTOR pathway is associated with the regenerative ability of peripheral nerves [ 18 ]. METTL13 knockdown reduces phosphorylation levels of AKT and mTOR [ 19 ]. EEF1A2 protects against apoptotic cell death by activating the PI3K/Akt pathway [ 20 ].…”

m6A RNA Methylation Regulators Contribute to Predict and as a Therapy Target of Pulmonary Fibrosis

“…The m6A methylation regulators consist of methyltransferases, blinding proteins, and demethylases. At present, methyltransferases contain METTL3 [ 5 ], METTL14 [ 6 ], RBM15 [ 7 ], WTAP [ 8 ], ZCH13 [ 9 ], KIAA1429 [ 10 ], HNRNPC [ 11 ], and blinding proteins include YTHDC2 [ 12 ], YTHDC1 [ 13 ], YTHDF1 [ 14 ], YTHDF2 [ 14 ], and demethylases have two proteins: FTO and ALKBH5 [ 9 , 12 ]. m6A modification plays a key role in biological development and disease occurrence.…”

An Interplay between Epigenetics and Translation in Oocyte Maturation and Embryo Development: Assisted Reproduction Perspective

“…The same enzyme is engaged in the angiogenesis of atherosclerotic mouse model embryos by upregulating vascular-endothelial growth factor (VEGF) [154] through m 6 A [155]. In zebrafish embryos, METTL3 regulated PHLPP2/mTOR-AKT signalling [156]. The recently published data have shown METTL3 direct interaction with the known p53 transcription factor that enhanced p53 stability and together cooperatively modified p53 targeted RNAs by m 6 A upon DNA damage [154]; METTL14 was found to be needed for embryonic post-implantation epiblast formation [149].…”