TY - JOUR
T1 - Pituitary Tumor Transforming Gene 1 Orchestrates Gene Regulatory Variation in Mouse Ventral Midbrain During Aging
AU - Gui, Yujuan
AU - Thomas, Mélanie H.
AU - Garcia, Pierre
AU - Karout, Mona
AU - Halder, Rashi
AU - Michelucci, Alessandro
AU - Kollmus, Heike
AU - Zhou, Cuiqi
AU - Melmed, Shlomo
AU - Schughart, Klaus
AU - Balling, Rudi
AU - Mittelbronn, Michel
AU - Nadeau, Joseph H.
AU - Williams, Robert W.
AU - Sauter, Thomas
AU - Buttini, Manuel
AU - Sinkkonen, Lasse
N1 - Funding Information:
We would like to thank Drs. Aur?lien Ginolhac and Anthoula Gaigneaux for their support with bioinformatic analysis EMBL Gene Core at Heidelberg for support with high-throughput sequencing, and Dr. Djalil Coowar (Animal Facility of University of Luxembourg) for help with breeding of experimental mice. KS would like to thank the animal caretakers at the Central Animal Facilities of the HZI for maintaining the mice. The computational analysis presented in this manuscript were carried out using the HPC facilities of the University of Luxembourg. Funding. LS and MB would like to thank the Luxembourg National Research Fund (FNR) for the support (FNR CORE C15/BM/10406131 grant). MM would like to thank the Luxembourg National Research Fund (FNR) for the support (FNR PEARL P16/BM/11192868 grant). KS would like to thank the support by intra-mural grants from the Helmholtz-Association (Program Infection and Immunity).
Publisher Copyright:
© Copyright © 2020 Gui, Thomas, Garcia, Karout, Halder, Michelucci, Kollmus, Zhou, Melmed, Schughart, Balling, Mittelbronn, Nadeau, Williams, Sauter, Buttini and Sinkkonen.
PY - 2020/9/23
Y1 - 2020/9/23
N2 - 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.
AB - 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.
KW - Pttg1
KW - aging
KW - midbrain
KW - mouse strains
KW - regulatory variation
UR - http://www.scopus.com/inward/record.url?scp=85092157692&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/33173537
U2 - 10.3389/fgene.2020.566734
DO - 10.3389/fgene.2020.566734
M3 - Article
C2 - 33173537
AN - SCOPUS:85092157692
SN - 1664-8021
VL - 11
JO - Frontiers in Genetics
JF - Frontiers in Genetics
M1 - 566734
ER -