Pituitary Tumor Transforming Gene 1 orchestrates gene regulatory variation in mouse ventral midbrain during aging
Frontiers in Genetics(2020)
Abstract
Background 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.
Results 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 TF, Pttg1 , showed significant differences among all 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 three-month-old C57BL/6J congenic Pttg1-/- mutants was only modestly altered, but shifted towards that of A/J and DBA/2J in nine-month-old mice. Principle component analysis 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.
Conclusion Taken together, our results show that Pttg1 contributes to gene regulatory variation between mouse strains and influences mouse midbrain transcriptome during aging.
### Competing Interest Statement
The authors have declared no competing interest.
* DAns
: dopaminergic neurons
DEGs
: differentially expressed genes
EDTA
: ethylenediamine tetraacetic acid
H3K4me3
: histone H3 lysine 4 trimethylation
LCSB
: Luxembourg Centre for Systems Biomedicine
log2FC
: log2-fold change
NP-40
: 4-Nonylphenyl-polyethylene glycol
PC
: principle component
PCA
: principle component analysis
PD
: Parkinson’s disease
PI
: Proteinase Inhibitor
Pttg1
: Pituitary Tumor Transforming Gene 1
RPKM
: Reads Per Kilobase Million
SDS
: sodium odecylsulfate
SN
: substantia nigra
TFs
: transcription factors
TSS
: transcription start sites
VTA
: ventral tegmental area.
MoreTranslated text
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined