Lack of telomerase gene expression in alternative lengthening of telomere cells is associated with chromatin remodeling of the hTR and hTERT gene promoters.
The presence of active telomere maintenance mechanisms in immortal cells allows the bypass of senescence by maintaining telomere length. In most immortal cell lines and tumors, telomere maintenance is attributable to telomerase reactivation. However, a number of immortal cell lines and tumors can achieve telomere maintenance in the absence of detectable telomerase activity by the alternative lengthening of telomere (ALT) mechanism. Epigenetic mechanisms have been implicated in the regulation of telomerase expression. We show that specific modifications within the chromatin environment of the hTR and hTERT promoters correlate with expression of hTR and hTERT in ALT, normal and telomerase-positive tumor cell lines. Lack of expression of hTR and hTERT in ALT cell lines is associated with histone H3 and H4 hypoacetylation and methylation of Lys9 histone H3. Conversely, hTR and hTERT expression in telomerase-positive cell lines is associated with hyperacetylation of H3 and H4 and methylation of Lys4 H3. Methylation of Lys20 H4 was not linked to gene expression but instead was specific to the hTR and hTERT promoters of ALT cells. This may provide an insight into the differences between ALT and telomerase-positive cells as well as a novel marker for the ALT phenotype. Treatment of normal and ALT cells with 5-azadeoxycytidine in combination with Trichostatin A caused chromatin remodeling of both promoters and reactivation of hTR and hTERT expression in ALT and normal cell lines. This data establishes a definite link between the chromatin environment of the telomerase gene promoters and transcriptional activity.
Atkinson
Stuart P
SP
Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, Bearsden, Glasgow, United Kingdom.
Hoare
Stacey F
SF
Glasspool
Rosalind M
RM
Keith
W Nicol
WN
D000107:Acetylation; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D004789:Enzyme Activation; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics*; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D019098:Telomerase; D008239:Lysine