GSE186009
Single-molecule chromatin architectures of human centromeres and telomeres
Centromeres and telomeres are essential structural components of eukaryotic genomes, and alterations in their structure and function contribute to various human diseases. Currently, our understanding of the chromatin architecture underlying centromeres and telomeres is limited owing to their highly repetitive DNA content. To overcome this, we applied long-read single-molecule chromatin fiber-sequencing (Fiber-seq) to a human cell line with a complete telomere-to-telomere (T2T) reference genome, resulting in single-nucleotide precise mapping of chromatin accessibility, nucleosome positioning, and transcription factor occupancy across 1.7 million intact ~16kb chromatin fibers - resolving the chromatin architecture for ~97% of human telomeric and centromeric DNA. We identify that the centromeric kinetochore binding region contains highly atypical chromatin that juxtaposes highly accessible and tightly compacted DNA - a feature unique to the kinetochore. This structure mirrors the alpha-satellite DNA repeat and appears driven via clustered CENP-B occupancy at hypo-CpG methylated repeats. In addition, telomeres often contain several kilobases of non-nucleosomal chromatin, and the transition between nucleosome-bound chromatin and the telomere cap is highly heterogeneous and often punctuated by CTCF-bound elements. Our findings uncover non-standard chromatin architectures as the predominant organizational structure of telomeres and the kinetochore binding region, and provide a framework for future studies of complete human epigenomes. Overall design: Single-molecule chromatin fiber-sequencing (Fiber-seq) of CHM13 cells using a complete reference genome. Single-molecule chromatin fiber-sequencing (Fiber-seq) of GM12878 cells using a complete reference genome.