A genetic memory initiates the epigenetic loop necessary to preserve centromere position.
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2020-10
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Centromeres are built on repetitive DNA sequences (CenDNA) and a specific chromatin enriched with the histone H3 variant CENP-A, the epigenetic mark that identifies centromere position. Here, we interrogate the importance of CenDNA in centromere specification by developing a system to rapidly remove and reactivate CENP-A (CENP-AOFF/ON ). Using this system, we define the temporal cascade of events necessary to maintain centromere position. We unveil that CENP-B bound to CenDNA provides memory for maintenance on human centromeres by promoting de novo CENP-A deposition. Indeed, lack of CENP-B favors neocentromere formation under selective pressure. Occasionally, CENP-B triggers centromere re-activation initiated by CENP-C, but not CENP-A, recruitment at both ectopic and native centromeres. This is then sufficient to initiate the CENP-A-based epigenetic loop. Finally, we identify a population of CENP-A-negative, CENP-B/C-positive resting CD4+ T cells capable to re-express and reassembles CENP-A upon cell cycle entry, demonstrating the physiological importance of the genetic memory.
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Hoffmann, Sebastian, Helena M Izquierdo, Riccardo Gamba, Florian Chardon, Marie Dumont, Veer Keizer, Solène Hervé, Shannon M McNulty, et al. (2020). A genetic memory initiates the epigenetic loop necessary to preserve centromere position. The EMBO journal, 39(20). p. e105505. 10.15252/embj.2020105505 Retrieved from https://hdl.handle.net/10161/24765.
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Beth Ann Sullivan
Research in the Sullivan Lab is focused on chromosome organization, with a specific emphasis on the genomics and epigenetics of the chromosomal locus called the centromere. The centromere is a specialized chromosomal site involved in chromosome architecture and movement, and when defective, is linked to cancer, birth defects, and infertility. The lab has described a unique type of chromatin (CEN chromatin) that forms exclusively at the centromere by replacement of core histone H3 by the centromeric histone variant CENP-A. Their studies also explore the composition of CEN chromatin and its relationship to the underlying highly repetitive alpha satellite DNA at the centromere. The Sullivan lab also discovered that genomic variation within alpha satellite DNA affects where the centromere is built and how well it functions. The Sullivan lab was part of the Telomere-to-Telomere T2T Consortium that used ultra long read sequencing and optical mapping to completely assemble each human chromosome, including through millions of basepairs of alpha satellite DNA at each centromere. Dr. Sullivan's group also builds human artificial chromosomes (HACs), using them as tools to test components required for a viable, transmissible chromosome and to study centromeric transcription and chromosome stability. The lab also studies formation and fate of chromosome abnormalities associated with birth defects, reproductive abnormalities, and cancer. Specifically, they study chromosomal abnormalities with two centromeres, called dicentric chromosomes. Originally described by Nobelist Barbara McClintock in the 1930s, dicentrics in most organisms are considered inherently unstable chromosomes because they trigger genome instability. However, dicentric chromosomes in humans are very stable and are often transmitted through multiple generations of a family. Using several approaches to experimentally reproduce dicentric chromosomes in human cells, the lab explores mechanisms of dicentric formation and their long-term fate.
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