Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescue

Cystic fibrosis (CF), caused by mutations to CFTR, leads to severe and progressive lung disease. The most common mutant, ΔF508-CFTR, undergoes proteasomal degradation, depleting its anion channel function. “Proteostasis” pathways, i.e. those relevant to protein processing and trafficking, are altered in cells with ΔF508-CFTR and can be modulated to partially rescue protein function. However, many details regarding proteostasis modulation, and its relevance to CF and ΔF508-CFTR rescue, remain poorly understood. To shed light on this, we re-analyzed public datasets characterizing transcription in CF vs. non-CF epithelia from human and pig airways, and also profiled established temperature, genetic, and chemical interventions that rescue ΔF508-CFTR. Meta-analysis yielded a core disease signature and two core rescue signatures. To interpret these, we compiled proteostasis pathways and an original “CFTR Gene Set Library”. The disease signature revealed differential regulation of mTORC1 signaling, endocytosis, and proteasomal degradation. Overlaying functional genomics data identified candidate mediators of low-temperature rescue, while multiple rescue strategies converged on activation of unfolded protein response pathways. Remarkably, however, C18, an analog of the CFTR corrector compound Lumacaftor, induced minimal transcriptional perturbation despite its rescue activity. This work elucidates the involvement of proteostasis in both disease and rescue perturbations while highlighting that not all CFTR rescue interventions act on transcription. Polarized air-liquid interface cultures of CFBE cells were treated to either knockdown of SIN3A, SYVN1 or NEED8, overexpression of miR-138, treated with corrector compound 18 (C18), or cultured at temperatures associated with improving ΔF508-CFTR trafficking.