Alternative Lengthening of Telomeres is characterized by reduced compaction of telomeric chromatin.
Proper telomeric chromatin configuration is thought to be essential for telomere homeostasis and stability. Previous studies in mouse suggested that loss of heterochromatin marks at telomeres might favor onset of Alternative Lengthening of Telomeres (ALT) pathway, by promoting homologous recombination. However, analysis of chromatin status at human ALT telomeres has never been reported. Here, using isogenic human cell lines and cellular hybrids, which rely either on telomerase or ALT to maintain telomeres, we show that chromatin compaction is reduced at ALT telomeres and this is associated with a global decrease in telomeric H3K9me3. This, subsequently, leads to upregulation of telomere transcription. Accordingly, restoration of a more condensed telomeric chromatin through telomerase-dependent elongation of short ALT telomeres reduces telomere transcription. We further show that loss of ATRX chromatin remodeler function, a frequent characteristic of ALT cells, is not sufficient to decrease chromatin condensation at telomeres nor to increase the expression of telomeric RNA species. These results offer new insight on telomeric chromatin properties in ALT cells and support the hypothesis that telomeric chromatin decondensation is important for ALT pathway.
Genetic and Epigenetic Alterations of Genomes, de Duve Institute, Catholic University of Louvain, Brussels 1200, Belgium and Telomeres and Cancer Laboratory, Equipe Labellisée Ligue, UMR3244-UPMC-Institut Curie, Paris 75248, France.
Harikleia
H
Episkopou
Irena
I
Draskovic
Amandine
A
Van Beneden
Gaëlle
G
Tilman
Marina
M
Mattiussi
Matthieu
M
Gobin
Nausica
N
Arnoult
Arturo
A
Londoño-Vallejo
Anabelle
A
Decottignies
D002460:Cell Line; D002843:Chromatin / Q000737:chemistry*; D004247:DNA / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000737:chemistry*; D059505:Telomere Homeostasis; D014158:Transcription, Genetic
D002843:Chromatin; D009687:Nuclear Proteins; D004247:DNA; D019098:Telomerase