The Rb1 tumour suppressor gene modifies telomeric chromatin architecture by regulating TERRA expression.
The tumour suppressor gene (Rb1) is necessary for the maintenance of telomere integrity in osteoblastic cells. We now show that the compaction of telomeric chromatin and the appropriate histone modifications of telomeric DNA are both dependent upon Rb1-mediated transcription of the telomere-derived long non-coding RNA TERRA. Expression of TERRA was reduced in Rb1 haploinsufficient cells, and further decreased by shRNA-mediated reduction of residual Rb1 expression. Restoration of Rb1 levels through lentiviral transduction was sufficient to reestablish both transcription of TERRA and condensation of telomeric chromatin. The human chromosome 15q TERRA promoter contains predicted retinoblastoma control elements, and was able to confer Rb1-dependent transcription upon a promoterless reporter gene. Chromatin immunoprecipitation revealed preferential binding of phosphorylated over non-phosphorylated Rb1 at the TERRA promoter. As Rb1-deficient cells show increased genomic instability we suggest that this novel non-canonical action of Rb1 may contribute to the tumour suppressive actions of Rb1.
INIBIC-Complejo Hospitalario Universitario A Coruña, Unidad de Genética, As Xubias, 84, 15006-A Coruña, Spain.
I
I
Gonzalez-Vasconcellos
Institut für Experimental Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
R
R
Schneider
Institute of Radiation Biology, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
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N
Anastasov
INIBIC-Complejo Hospitalario Universitario A Coruña, Unidad de Genética, As Xubias, 84, 15006-A Coruña, Spain.
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S
Alonso-Rodriguez
Institute of Radiation Biology, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
B
B
Sanli-Bonazzi
INIBIC-Complejo Hospitalario Universitario A Coruña, Unidad de Genética, As Xubias, 84, 15006-A Coruña, Spain.|Laboratorio de Genética Molecular y Radiobiología, Centro Oncológico de Galicia, 15009-A Coruña, Spain.
J L
JL
Fernández
Institute of Radiation Biology, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
M J
MJ
Atkinson
D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism; D002884:Chromosomes, Human, Pair 15; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D042822:Genomic Instability; D006570:Heterochromatin / Q000378:metabolism / Q000648:ultrastructure*; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000378:metabolism* / Q000648:ultrastructure; D014158:Transcription, Genetic
D006570:Heterochromatin; D006657:Histones; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein