TRAIN (Transcription of Repeats Activates INterferon) in response to chromatin destabilization induced by small molecules in mammalian cells.
Katerina LeonovaAlfiya SafinaElimelech NesherPoorva SandleshRachel PrattCatherine BurkhartBrittany LipchickIlya GitlinCostakis FrangouIgor KomanJianmin WangKirill KirsanovMarianna G YakubovskayaAndrei V GudkovKaterina V GurovaPublished in: eLife (2018)
Cellular responses to the loss of genomic stability are well-established, while how mammalian cells respond to chromatin destabilization is largely unknown. We previously found that DNA demethylation on p53-deficient background leads to transcription of repetitive heterochromatin elements, followed by an interferon response, a phenomenon we named TRAIN (Transcription of Repeats Activates INterferon). Here, we report that curaxin, an anticancer small molecule, destabilizing nucleosomes via disruption of histone/DNA interactions, also induces TRAIN. Furthermore, curaxin inhibits oncogene-induced transformation and tumor growth in mice in an interferon-dependent manner, suggesting that anticancer activity of curaxin, previously attributed to p53-activation and NF-kappaB-inhibition, may also involve induction of interferon response to epigenetic derepression of the cellular 'repeatome'. Moreover, we observed that another type of drugs decondensing chromatin, HDAC inhibitor, also induces TRAIN. Thus, we proposed that TRAIN may be one of the mechanisms ensuring epigenetic integrity of mammalian cells via elimination of cells with desilenced chromatin.
Keyphrases
- transcription factor
- gene expression
- dendritic cells
- dna damage
- dna methylation
- small molecule
- high speed
- genome wide
- circulating tumor
- induced apoptosis
- cell free
- single molecule
- signaling pathway
- immune response
- high frequency
- endoplasmic reticulum stress
- copy number
- skeletal muscle
- lps induced
- adipose tissue
- pi k akt
- nucleic acid
- diabetic rats
- circulating tumor cells