Life sciences : Biochemistry, biophysics & molecular biology
Systems Biomedicine
http://hdl.handle.net/10993/44345
Pituitary Tumor Transforming Gene 1 Orchestrates Gene Regulatory Variation in Mouse Ventral Midbrain During Aging
English
Gui, Yujuan[University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Thomas, Mélanie H.[Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg]
Garcia, Pierre[Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg > > > ; National Center of Pathology, Laboratoire National de Santé, Dudelange, Luxembourg > > > ; Luxembourg Centre of Neuropathology, Dudelange, Luxembourg]
Karout, Mona[Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg]
Halder, Rashi[University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Michelucci, Alessandro[University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > >]
Kollmus, Heike[Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany]
Zhou, Cuiqi[Cedars Sinai Medical Centre, Los Angeles, CA, United States]
Melmed, Shlomo[Cedars Sinai Medical Centre, Los Angeles, CA, United States]
Schughart, Klaus[Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany > > > ; Department of Infection Genetics, University of Veterinary Medicine Hannover, Hanover, Germany > > > ; Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, United States]
Balling, Rudolf[University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Mittelbronn, Michel[University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Nadeau, Joseph H.[Pacific Northwest Research Institute, Seattle, WA, United States > > > ; Maine Medical Center Research Institute, Scarborough, ME, United States]
Williams, Robert W.[Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, United States]
Sauter, Thomas[University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Buttini, Manuel[University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Sinkkonen, Lasse[University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
[en] 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 (∼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 in Pttg1 expression were accompanied by consistent alterations in histone H3 lysine 4 trimethylation at Pttg1 transcription start site. The ventral midbrain transcriptome of 3-month-old C57BL/6J congenic Pttg1–/– 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 that Pttg1 contributes to gene regulatory variation between mouse strains and influences mouse midbrain transcriptome during aging.
[University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
