Understanding m6A’s role in the myometrium during gestation

Epigenetic modifications, such as DNA methylation, mainly affects the function of genes through regulating the transcription or translation processes, without altering the DNA sequences. The regulation of m6A modification is dynamic and reversible and is established by m6A methyltransferases (“writers”), such as methyltransferase-like protein 3 (METTL3). It is removed by m6A demethylases (“erasers”), such as α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5). The effects of m6A modification on RNA metabolism depend on the recognition by different m6A -binding proteins (“readers”), including the YT521-B homology (YTH) domain family and the heterogeneous nuclear ribonucleoproteins (HNRNPs). We believe that splicing directed by m6A methylation plays a significant role in regulating the physiology of the pregnant myometrium through alternative splicing of pre-mRNAs, facilitating rapid expansion and plasticity of the genome, producing an altered active proteome allowing for the transition from a quiescent to laboring myometrial compartment. Western blot analysis of pregnant mouse uteri from mid gestation to term in labor revealed distinct and corollary gestational modifications in the reader and writers METTL3, hnRNPC and YTHDC1, which spiked at mid gestation and again at term correlating with m6A labeling and previously observed increases in myometrial splicing events. In contrast as expected the eraser ALKBH5 levels declined towards term. Future analysis will examine if these gestational changes are hormonally regulated. We believe that alternative splicing and changes in the epi-transcriptome through m6A regulation are an underlying mechanism involved in normal term labor and understanding these phenomena may lead to development of an effective therapeutic for preterm labor

Understanding m6A’s role in the myometrium during gestation

Epigenetic modifications, such as DNA methylation, mainly affects the function of genes through regulating the transcription or translation processes, without altering the DNA sequences. The regulation of m6A modification is dynamic and reversible and is established by m6A methyltransferases (“writers”), such as methyltransferase-like protein 3 (METTL3). It is removed by m6A demethylases (“erasers”), such as α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5). The effects of m6A modification on RNA metabolism depend on the recognition by different m6A -binding proteins (“readers”), including the YT521-B homology (YTH) domain family and the heterogeneous nuclear ribonucleoproteins (HNRNPs). We believe that splicing directed by m6A methylation plays a significant role in regulating the physiology of the pregnant myometrium through alternative splicing of pre-mRNAs, facilitating rapid expansion and plasticity of the genome, producing an altered active proteome allowing for the transition from a quiescent to laboring myometrial compartment. Western blot analysis of pregnant mouse uteri from mid gestation to term in labor revealed distinct and corollary gestational modifications in the reader and writers METTL3, hnRNPC and YTHDC1, which spiked at mid gestation and again at term correlating with m6A labeling and previously observed increases in myometrial splicing events. In contrast as expected the eraser ALKBH5 levels declined towards term. Future analysis will examine if these gestational changes are hormonally regulated. We believe that alternative splicing and changes in the epi-transcriptome through m6A regulation are an underlying mechanism involved in normal term labor and understanding these phenomena may lead to development of an effective therapeutic for preterm labor