Extrachromosomal DNA (ecDNA) is a major driver of cancer pathogenesis, however, its spatial organization in the nucleus is not currently understood. Here we show that ecDNAs, in contrast to chromosomal DNA, preferentially localize to the nuclear periphery yet resist peripheral gene silencing. Single-molecule multi-omic sequencing and imaging-based CRISPR screening demonstrate enhanced ecDNA hub formation, H3K27ac and H3K9me3 bivalency, late DNA replication, long-range CpG hypomethylation, and increased transcriptional output when ecDNAs localize to the nuclear periphery. EcDNA anchors to the nuclear lamina through H3K9me3-dependent interactions with the Lamin B Receptor (LBR), which if interrupted, results in inward migration of ecDNA particles, reduced ecDNA congregation, and decreased transcription of ecDNA-encoded genes. These results reveal inherent advantages of the spatial organization of ecDNA that are not available to chromosomal DNA, enhancing ecDNA congregation and amplifying oncogenic transcriptional output, by localizing to the nuclear periphery of cancer cells.
Yan-Bo Wang, Xiao-Wei Yan, Natasha E. Weiser et al.· bioRxiv· 0 citations
SUMMARY Human genome sequencing typically relies on mapping reads to a reference genome to call variants, but this approach introduces technical biases, excluding duplicated and structurally polymorphic regions of the genome. To overcome this, we present a telomere-to-telomere genome benchmark with near-perfect accuracy across 99.4% of the diploid HG002 genome. This benchmark adds 701.4 Mb of autosomal sequence and both sex chromosomes (216.8 Mb), which were absent from prior benchmarks. We annotated genes and repeats on both haplotypes, including 19,956 protein-coding genes on the maternal haplotype and 19,190 on the paternal haplotype, and developed new methods to measure the accuracy of reads, phased variant call sets, and assemblies against a diploid reference. Genome-wide analyses show that de novo assembly resolves 2%–7% more sequence and outperforms variant calling accuracy by an order of magnitude, expanding the reach of genomic medicine to the entire genome and enabling a new era of personalized genomics.
Nancy F. Hansen, Nathan Dwarshuis, Hyun Joo Ji et al.· Cell· 7 citations
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