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In cancer cells, histone H3 variant CENP-A is innately overexpressed and mislocalized to regions outside centromeres, typically to chromosome arms and telomeres. Transcription and transcripts of specific oncogenic lncRNAs could serve as a recruitment signal for CENP-A mislocalization. Thus, the oncogenic lncRNA-based mechanism of CENP-A mislocalization can generate aberrant epigenetic signatures resulting in chromosome breaks and amplification in the cancer epigenome.

https://www.science.org/doi/10.1126/sciadv.abl5621

Abstract

Chromosome instability is a critical event in cancer progression. Histone H3 variant CENP-A plays a fundamental role in defining centromere identity, structure, and function but is innately overexpressed in several types of solid cancers. In the cancer background, excess CENP-A is deposited ectopically on chromosome arms, including 8q24/cMYC locus, by invading transcription-coupled H3.3 chaperone pathways. Up-regulation of lncRNAs in many cancers correlates with poor prognosis and recurrence in patients. We report that transcription of 8q24-derived oncogenic lncRNAs plays an unanticipated role in altering the 8q24 chromatin landscape by H3.3 chaperone–mediated deposition of CENP-A–associated complexes. Furthermore, a transgene cassette carrying specific 8q24-derived lncRNA integrated into a naïve chromosome locus recruits CENP-A to the new location in a cis-acting manner. These data provide a plausible mechanistic link between locus-specific oncogenic lncRNAs, aberrant local chromatin structure, and the generation of new epigenetic memory at a fragile site in human cancer cells.

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Schematic representation of H1 binding modes. Image credit: Ankita Saha and Yamini Dalal.

Taken from Open Biology article “A Glitch in the Snitch: the role of linker histone H1 in shaping the epigenome in normal and diseased cells” DOI: 10.1098/rsob.210124

Abstract

Histone H1s or the linker histones are a family of dynamic chromatin compacting proteins that are essential for higher-order chromatin organization. These highly positively charged proteins were previously thought to function solely as repressors of transcription. However, over the last decade, there is a growing interest in understanding this multi-protein family, finding that not all variants act as repressors. Indeed, the H1 family members appear to have distinct affinities for chromatin and may potentially affect distinct functions. This would suggest a more nuanced contribution of H1 to chromatin organization. The advent of new technologies to probe H1 dynamics in vivo, combined with powerful computational biology, and in vitro imaging tools have greatly enhanced our knowledge of the mechanisms by which H1 interacts with chromatin. This family of proteins can be metaphorically compared to the Golden Snitch from the Harry Potter series, buzzing on and off several regions of the chromatin, in combat with competing transcription factors and chromatin remodellers, thereby critical to the epigenetic endgame on short and long temporal scales in the life of the nucleus. Here, we summarize recent efforts spanning structural, computational, genomic and genetic experiments which examine the linker histone as an unseen architect of chromatin fibre in normal and diseased cells and explore unanswered fundamental questions in the field.

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This special issue “Diving into chromatin structure across space and time” highlights the application of cutting-edge approaches to further illuminate transactions that occur on, and by, the chromatin fiber. Appropriately for this year of covid, where virtual life is a simulacrum of reality, we start at one end of the scale - computational modeling of dynamic nucleoprotein complexes.

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Chaperone HJURP drives the proper loading of protein CENP-A to the centromere of a chromosome. The effect of HJURP on CENP-A's structural dynamics are observed and explained using dual-resolution in silico simulations, while in vivo experiments demonstrate how CENP-A mutations influence its specific localization in human cells.

Abstract

Histone proteins are essential for the organization, expression, and inheritance of genetic material for eukaryotic cells. A centromere-specific H3 histone variant, centromere protein A (CENP-A), shares about 50% amino acid sequence identity with H3. CENP-A is required for packaging the centromere and for the proper separation of chromosomes during mitosis. Despite their distinct biological functions, previously reported crystal structures of the CENP-A/H4 and H3/H4 dimers reveal a high degree of similarity. In this work, we characterize the structural dynamics of CENP-A/H4 and H3/H4 dimers based on a dual-resolution approach, using both microsecond-scale explicit-solvent all-atom and coarse-grained (CG) molecular dynamics (MD) simulations. Our data show that the H4 histone is significantly more rigid compared with the H3 histone and its variant CENP-A, hence, serving as a reinforcing structural element within the histone core. We report that the CENP-A/H4 dimer is significantly more dynamic than its canonical counterpart H3/H4, and our results provide a physical explanation for this flexibility. Further, we observe that the centromere-specific chaperone Holliday Junction Recognition Protein (HJURP) stabilizes the CENP-A/H4 dimer by forming a specific electrostatic interaction network. Finally, replacing CENP-A S68 with E68 disrupts the binding interface between CENP-A and HJURP in all-atom MD simulation, and consistently, in vivo experiments demonstrate that replacing CENP-A S68 with E68 disrupts CENP-A’s localization to the centromere. Based on all our results, we propose that, during the CENP-A/H4 deposition process, the chaperone HJURP protects various substructures of the dimer, serving both as a folding and binding chaperone.