SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes.
Ken TajimaToshifumi YaeSarah JavaidOliver H TamValentine ComaillsRobert MorrisBen S WittnerMingzhu LiuAmanda EngstromFumiyuki TakahashiJoshua C BlackSridhar RamaswamyToshihiro ShiodaMolly HammellDaniel A HaberJohnathan R WhetstineShyamala MaheswaranPublished in: Nature communications (2015)
Expression of the p53-inducible antiproliferative gene BTG2 is suppressed in many cancers in the absence of inactivating gene mutations, suggesting alternative mechanisms of silencing. Using a shRNA screen targeting 43 histone lysine methyltransferases (KMTs), we show that SETD1A suppresses BTG2 expression through its induction of several BTG2-targeting miRNAs. This indirect but highly specific mechanism, by which a chromatin regulator that mediates transcriptional activating marks can lead to the downregulation of a critical effector gene, is shared with multiple genes in the p53 pathway. Through such miRNA-dependent effects, SETD1A regulates cell cycle progression in vitro and modulates tumorigenesis in mouse xenograft models. Together, these observations help explain the remarkably specific genetic consequences associated with alterations in generic chromatin modulators in cancer.
Keyphrases
- cell cycle
- genome wide
- genome wide identification
- dna methylation
- transcription factor
- cell proliferation
- poor prognosis
- copy number
- signaling pathway
- gene expression
- cancer therapy
- small molecule
- genome wide analysis
- dna damage
- papillary thyroid
- dendritic cells
- immune response
- regulatory t cells
- oxidative stress
- drug delivery
- squamous cell
- amino acid
- type iii