Pituitary Tumor Transforming Gene 1Orchestrates Gene Regulatory Variation in Mouse Ventral Midbrain During Aging

Dopaminergic neurons in the midbrain are of particular interest due to their role in diseases such as Parkinson's disease and schizophrenia. Genetic variation between individuals can affect the integrity and function of dopaminergic neurons but the DNA variants and molecular cascades modulating dopaminergic neurons and other cells types of ventral midbrain remain poorly defined. Three genetically diverse inbred mouse strains - C57BL/6J, A/J, and DBA/2J - differ significantly in their genomes (similar to 7 million variants), motor and cognitive behavior, and susceptibility to neurotoxins. To further dissect the underlying molecular networks responsible for these variable phenotypes, we generated RNA-seq and ChIP-seq data from ventral midbrains of the 3 mouse strains. We defined 1000-1200 transcripts that are differentially expressed among them. These widespread differences may be due to altered activity or expression of upstream transcription factors. Interestingly, transcription factors were significantly underrepresented among the differentially expressed genes, and only one transcription factor,Pttg1, showed significant differences between all three strains. The changes inPttg1expression were accompanied by consistent alterations in histone H3 lysine 4 trimethylation atPttg1transcription start site. The ventral midbrain transcriptome of 3-month-old C57BL/6J congenicPttg1(-/-)mutants was only modestly altered, but shifted toward that of A/J and DBA/2J in 9-month-old mice. Principle component analysis (PCA) identified the genes underlying the transcriptome shift and deconvolution of these bulk RNA-seq changes using midbrain single cell RNA-seq data suggested that the changes were occurring in several different cell types, including neurons, oligodendrocytes, and astrocytes. Taken together, our results show thatPttg1contributes to gene regulatory variation between mouse strains and influences mouse midbrain transcriptome during aging.