Reprogramming chromosome ends by functional histone acetylation

Cancers harness embryonic programs to evade aging and promote survival. Normally, sequences at chromosome ends called telomeres, shorten with cell division, and function as a countdown clock to limits cell replication. Therefore, a crucial aspect of cancerous transformation is avoiding replicative aging, by activation of telomere repair programs. In mouse embryonic stem cells (mESCs), the transient expression of the gene Zscan4, correlates with chromatin de-condensation and telomere extension. Head and neck cancers reactivate ZSCAN4, which in turn regulates the cancer stem cell (CSCs) phenotype. Our new study reveals a novel role for human ZSCAN4 in facilitating functional histone H3 acetylation at the telomere chromatin. Next-generation sequencing reveals ZSCAN4 enrichment at chromosome ends and its pivotal role in facilitating histone H3 acetylation at telomeres. These epigenetic changes correlate with ZSCAN4-induced telomere elongation, while CRISPR/Cas9 knockout of ZSCAN4 leads to telomere shortening in cancer cells. Our study elucidates the intricate involvement of ZSCAN4 in modulating telomere histone acetylation, and its interaction with telomeric proteins. These findings suggest ZSCAN4 induction as a novel link between cancer stemness and telomere maintenance. Future strategies aimed at blocking ZSCAN4 may provide new therapeutic approaches to effectively target cancer stem cells and limit their replicative lifespan. tet-FLAG-ZSCAN4-Tu167 cells were grown to 50% confluency and incubated for 48 hours with or without 1 µg/ml doxycycline. ChIP was done using the Pierce Magnetic ChIP Kit (Thermo Scientific) according to the manufacturer’s instructions. Antibodies used for ChIP: Anti-ZSCAN4 (10 µg) (Origene); anti-H3K14ac and H3K18ac (4 µg); Cell signaling), and the provided anti-RNA Polymerase II (1µg) and a Rabbit IgG (10 µg) were used as additional controls.