Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin.
Here, we show a role for the RB1 family proteins in directing full heterochromatin formation. Mouse embryonic fibroblasts that are triply deficient for RB1 (retinoblastoma 1), RBL1 (retinoblastoma-like 1) and RBL2 (retinoblastoma-like 2) - known as TKO cells - show a marked genomic instability, which is coincidental with decreased DNA methylation, increased acetylation of histone H3 and decreased tri-methylation of histone H4 at lysine 20 (H4K20). Chromatin immunoprecipitation showed that H4K20 tri-methylation was specifically decreased at pericentric and telomeric chromatin. These defects are independent of E2F family function. Indeed, we show a direct interaction between the RB1 proteins and the H4K20 tri-methylating enzymes Suv4-20h1 and Suv4-20h2, indicating that the RB1 family has a role in controlling H4K20 tri-methylation by these histone methyltransferases. These observations indicate that the RB1 family is involved in maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin, linking tumour suppression and the epigenetic definition of chromatin.
Gonzalo
Susana
S
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid E-28029, SPAIN.
García-Cao
Marta
M
Fraga
Mario F
MF
Schotta
Gunnar
G
Peters
Antoine H F M
AH
Cotter
Shane E
SE
Eguía
Raúl
R
Dean
Douglas C
DC
Esteller
Manel
M
Jenuwein
Thomas
T
Blasco
María A
MA
D000818:Animals; D019175:DNA Methylation; D005347:Fibroblasts / Q000378:metabolism; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009687:Nuclear Proteins / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000502:physiology*; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130
D006570:Heterochromatin; D006657:Histones; D009687:Nuclear Proteins; D011506:Proteins; C489485:Rbl1 protein, mouse; C493838:Rbl2 protein, mouse; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130