Mice deficient of Myc super-enhancer region reveal differential control mechanism between normal and pathological growth.
Kashyap DaveInderpreet SurJian YanJilin ZhangEevi KaasinenFan ZhongLeander BlaasXiaoze LiShabnam KharaziCharlotte GustafssonAyla De PaepeRobert MånssonJussi TaipalePublished in: eLife (2017)
The gene desert upstream of the MYC oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kb deletion of the entire MYC upstream super-enhancer region in mice results in 50% to 80% decrease in Myc expression in multiple tissues. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture. These results reveal that only cells whose MYC activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer chemoprevention and therapy.
Keyphrases
- transcription factor
- genome wide
- induced apoptosis
- endothelial cells
- binding protein
- high fat diet induced
- cell cycle arrest
- papillary thyroid
- copy number
- poor prognosis
- gene expression
- stem cells
- wild type
- dna methylation
- single cell
- metabolic syndrome
- bone marrow
- pluripotent stem cells
- young adults
- insulin resistance
- smoking cessation