TERRA regulates DNA G-quadruplex formation and ATRX recruitment to chromatin

Abstract

The genome consists of non-B-DNA structures such as G-quadruplexes (G4) that are involved in the regulation of genome stability and transcription. Telomeric-repeat containing RNA (TERRA) is capable of folding into G-quadruplex and interacting with chromatin remodeler ATRX. Here we show that TERRA modulates ATRX occupancy on repetitive sequences and over genes, and maintains DNA G-quadruplex structures at TERRA target and non-target sites in mouse embryonic stem cells. TERRA prevents ATRX from binding to subtelomeric regions and represses H3K9me3 formation. G4 ChIP-seq reveals that G4 abundance decreases at accessible chromatin regions, particularly at transcription start sites (TSS) after TERRA depletion; such G4 reduction at TSS is associated with elevated ATRX occupancy and differentially expressed genes. Loss of ATRX alleviates the effect of gene repression caused by TERRA depletion. Immunostaining analyses demonstrate that knockdown of TERRA diminishes DNA G4 signals, whereas silencing ATRX elevates G4 formation. Our results uncover an epigenetic regulation by TERRA that sequesters ATRX and preserves DNA G4 structures.

ATRX/DAXX: Guarding the Genome against the Hazards of ALT

“…Unsurprisingly, R-loops and G4s are highly associated at TERRA binding sites. Consistent with this observation, knockdown of TERRA decreases genomic G4s, and knockdown of ATRX increases them [ 83 ], suggesting that TERRA antagonizes ATRX from its role in resolving G4 structures. Thus, TERRA levels may act to modulate ATRX binding to genomic targets.…”

“…In mammals, TERRA is observed to promote maintenance of telomeric heterochromatin through interactions with TRF2, PRC2, and SUV39H1 [ 77 , 81 , 82 ]. There is evidence that TERRA acts as an ATRX “sponge”, titrating ATRX away from DNA targets—depleting TERRA increases ATRX occupancy at rDNA, telomeres, sub-telomeres, and repetitive sequences in mESCs [ 66 , 83 ].…”

An immune signature to predict the prognosis of ATRX-wildtype glioma patients and guide immune checkpoint blockade therapy

“…The N-terminal ATRX – DNA methyltransferase 3 – DNA methyltransferase 3-like (‘ADD’) domain contains a plant homeodomain and a GATA zinc finger structure [ 15 ]. The GATA zinc finger can bind to DNA or chromatin, while the plant homeodomain participates in chromatin regulation and transcription [ 16 , 17 ].…”

The regulations of telomerase reverse transcriptase (TERT) in cancer

“…Significantly, a high level of G-rich DNA exists throughout the genome, especially in the promoter regions of oncogenes. Therefore, G4 ligands have several risks when used in telomerase inhibition and may have a significant offtarget effect [160][161][162].…”