Cancer-induced FOXP1 disrupts and reprograms skeletal muscle circadian transcription in cachexia [ChIP-seq]
Cancer cachexia is a debilitating metabolic disorder characterized by involuntary loss of body and muscle mass, leading to increased morbidity and mortality. We previously found that Forkhead box P1 (FoxP1) upregulation in skeletal muscle causes muscle wasting and is required for muscle wasting in response to cancer. However, transcriptional networks targeted by FoxP1 in skeletal muscles undergoing cancer-induced wasting remain largely unknown. Here, we identify FoxP1 as a key disruptor of the skeletal muscle clock in response to cancer, that reprograms circadian patterns of gene expression at cachexia onset. Specifically, we show that cancer-induced FoxP1 rewires the skeletal muscle circadian transcriptome towards pathways associated with muscle wasting and disrupts the temporal patterning of pathways governing glucose, lipid, and oxidative metabolism. These findings thus implicate cancer/disease-specific functions of FOXP1 in the disruption and reprograming of the skeletal muscle circadian transcriptome which may contribute to muscle wasting and the development of cachexia. Overall design: Gastrocnemius-plantaris muscle complexes were isolated and pooled from the hind limbs of 10-week-old C57BL/6J male mice following a 30-hour fast (n=2), and 12-week-old C57BL/6J male mice with or without KPC pancreatic tumors (n=2 mice/group). Isolated whole muscle samples were sent to Active Motif (Carlsbad, CA) for ChIP-sequencing. A ChIP reaction was carried out using 15 µg of skeletal muscle chromatin and anti-FoxP1 antibody (Millipore, ABE68, RRID:AB_10631734). ChIP DNA sequences generated by a standard Illumina ChIP-sequencing library were aligned to the mouse genome (mm10). Binding events were called and identified using MACS with the manufacturer default cutoff of P < 1 × 10-7. De novo motifs were identified via HOMER.