Epigenetic regulation of the INK4b-ARF-INK4a locus: in sickness and in health.
The INK4b-ARF-INK4a locus encodes for two cyclin-dependent kinase inhibitors, p15(INK4b) and p16(INK4a) and a regulator of the p53 pathway, ARF. In addition ANRIL, a non-coding RNA, is also transcribed from the locus. ARF, p15(INK4b) and p16(INK4a) are well-established tumor suppressors which function is frequently disabled in human cancers. Recent studies showed that single nucleotide polymorphisms mapping in the vicinity of ANRIL are linked to a wide spectrum of conditions, including cardiovascular disease, ischemic stroke, type 2 diabetes, frailty and Alzheimer's disease. The INK4b-ARF-INK4a locus is regulated by Polycomb repressive complexes (PRCs), and its expression can be invoked by activating signals. Other epigenetic modifiers such as the histone demethylases JMJD3 and JHDM1B, the SWI/SNF chromatin remodeling complex and DNA methyltransferases regulate the locus interplaying with PRCs. In view of the intimate involvement of the INK4b-ARF-INK4a locus on disease, to understand its regulation is the first step for manipulate it to therapeutic benefit.
Popov
Nikolay
N
Cell Proliferation Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, London, UK.
Gil
Jesús
J
D020727:ADP-Ribosylation Factors / Q000096:biosynthesis* / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000096:biosynthesis* / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D015254:DNA Modification Methylases; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D016193:G1 Phase / Q000235:genetics; D056426:Genetic Loci; D056466:Histone Demethylases; D006801:Humans; D063146:Polycomb-Group Proteins; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C493966:CDKN2B protein, human; D002843:Chromatin; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D063146:Polycomb-Group Proteins; D022661:RNA, Untranslated; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D056466:Histone Demethylases; D015254:DNA Modification Methylases; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D020727:ADP-Ribosylation Factors