Telomere interactions and structural variants in ALT cells revealed with TelSPRITE

Area of Science:

• Genomics
• Cancer Biology
• Epigenetics

Background:

• Telomere maintenance is crucial for cancer cell survival.
• Alternative Lengthening of Telomeres (ALT) is a telomerase-independent pathway.
• ALT tumors exhibit extensive genomic rearrangements, including telomere repeat-containing structural variants.

Purpose of the Study:

• To investigate the spatial association of genomic loci with telomeres in ALT tumors.
• To identify genomic regions prone to telomere recombination events in ALT.
• To understand the 3D genome organization and structural variants in ALT cells.

Main Methods:

• Development of TelSPRITE, a novel method to analyze telomere contact frequencies from SPRITE data.
• Identification and binning of reads containing telomere repeats.
• Quantification of spatial contacts between telomeres and the rest of the genome using long-read sequencing data.

Main Results:

• Telomere contact frequency decreases with chromosomal distance, consistent with 3D genome organization principles.
• Telomere contacts are enriched near centromeres, suggesting heterochromatin clustering.
• ALT cell lines show global telomere enrichment and specific intrachromosomal contact spikes, indicative of structural variants.

Conclusions:

• TelSPRITE effectively profiles telomeric spatial organization and genomic rearrangements in ALT cells.
• The study provides insights into the genetic evolution and 3D genome architecture of ALT tumors.
• Findings highlight the role of telomere-associated structural variants in ALT cancer progression.