Big data analytics for MerTK genomics reveals its double-edged sword functions in human diseases

Rationale: MER proto-oncogene tyrosine kinase (MerTK) is a key receptor for the clearance of apoptotic cells (efferocytosis) and plays important roles in redox-related human diseases. We will explore MerTK biology in human cells, tissues, and diseases based on big data analytics. Methods: The human RNA-seq and scRNA-seq data about 42,700 samples were from NCBI Gene Expression Omnibus and analyzed by QIAGEN Ingenuity Pathway Analysis (IPA) with about 170,000 crossover analysis. MerTK expression was quantified as Log2 (FPKM + 0.1). Results: We found that, in human cells, MerTK is highly expressed in macrophages, monocytes, progenitor cells, alpha -beta T cells, plasma B cells, myeloid cells, and endothelial cells (ECs). In human tissues, MerTK has higher expression in plaque, blood vessels, heart, liver, sensory system, artificial tissue, bone, adrenal gland, central nervous system (CNS), and connective tissue. Compared to normal conditions, MerTK expression in related tissues is altered in many human diseases, including cardiovascular diseases, cancer, and brain disorders. Interestingly, MerTK expression also shows sex differences in many tissues, indicating that MerTK may have different impact on male and female. Finally, based on our proteomics from primary human aortic ECs, we validated the functions of MerTK in several human diseases, such as cancer, aging, kidney failure and heart failure. Conclusions: Our big data analytics suggest that MerTK may be a promising therapeutic target, but how it should be modulated depends on the disease types and sex differences. For example, MerTK inhibition emerges as a new strategy for cancer therapy due to it counteracts effect on anti -tumor immunity, while MerTK restoration represents a promising treatment for atherosclerosis and myocardial infarction as MerTK is cleaved in these disease conditions.