FAM120A couples SREBP-dependent transcription and splicing of lipogenesis enzymes downstream of mTORC1

The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that stimulates macromolecule synthesis via insulin, growth factors, and oncogenic signals. mTORC1 activates anabolic pathways by inducing posttranslational modifications of metabolic enzymes, and by regulating expression through transcription and mRNA processing. However, mechanisms of how mTORC1 orchestrates these tightly connected processes remain unclear. Here, we identify FAM120A as a transcriptional co-activator that couples transcription and splicing of lipid synthesis enzymes downstream of mTORC1-SRPK2 signaling. Mechanistically, the mTORC1-activated SRPK2 phosphorylates a splicing factor SRSF1, enhancing its binding to FAM120A. FAM120A directly interacts with a lipogenic transcription factor SREBP1 at active promoters, thereby bridging newly transcribed lipogenic genes to the RNA splicing machinery. This multi-protein complex regulated by mTORC1 promotes efficient splicing and stability of lipogenic transcripts, resulting in fatty acid synthesis and cancer cell proliferation. These results elucidate FAM120A as a critical transcription co-factor that connects mTORC1-dependent gene regulation programs for anabolic cell growth. Overall design: We performed a deep RNA sequencing to determine the effect of FAM120A and SRSF1 knockdown on global gene expression and RNA splicing.