Deciphering Obesity-Related Gene Clusters Unearths SOCS3 Immune Infiltrates and 5mC/m6A Modifiers in Ossification of Ligamentum Flavum Pathogenesis

The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

N(6)-methyladenosine (m(6)A) is the most abundant internal modification in mammalian mRNA. This modification is reversible and non-stoichiometric and adds another layer to the dynamic control of mRNA metabolism. The stability of m(6)A-modified mRNA is regulated by an m(6)A reader protein, human YTHDF2, which recognizes m(6)A and reduces the stability of target transcripts. Looking at additional functional roles for the modification, we find that another m(6)A reader protein, human YTHDF1, actively promotes protein synthesis by interacting with translation machinery. In a unified mechanism of m(6)A-based regulation in the cytoplasm, YTHDF2-mediated degradation controls the lifetime of target transcripts, whereas YTHDF1-mediated translation promotion increases translation efficiency, ensuring effective protein production from dynamic transcripts that are marked by m(6)A. Therefore, the m(6)A modification in mRNA endows gene expression with fast responses and controllable protein production through these mechanisms.

Epigenetics is one of the most rapidly expanding fields in biology. The recent characterization of a human DNA methylome at single nucleotide resolution, the discovery of the CpG island shores, the finding of new histone variants and modifications, and the unveiling of genome-wide nucleosome positioning maps highlight the accelerating speed of discovery over the past two years. Increasing interest in epigenetics has been accompanied by technological breakthroughs that now make it possible to undertake large-scale epigenomic studies. These allow the mapping of epigenetic marks, such as DNA methylation, histone modifications and nucleosome positioning, which are critical for regulating gene and noncoding RNA expression. In turn, we are learning how aberrant placement of these epigenetic marks and mutations in the epigenetic machinery is involved in disease. Thus, a comprehensive understanding of epigenetic mechanisms, their interactions and alterations in health and disease, has become a priority in biomedical research.