Shaping Chromatin in the Nucleus: The Bricks and the Architects

Abstract

Chromatin organization in the nucleus provides a vast repertoire of information in addition to that encoded genetically. Understanding how this organization impacts genome stability and influences cell fate and tumorigenesis is an area of rapid progress. Considering the nucleosome, the fundamental unit of chromatin structure, the study of histone variants (the bricks) and their selective loading by histone chaperones (the architects) is particularly informative. Here, we report recent advances in understanding how relationships between histone variants and their chaperones contribute to tumorigenesis using cell lines and Xenopus development as model systems. In addition to their role in histone deposition, we also document interactions between histone chaperones and other chromatin factors that govern higher-order structure and control DNA metabolism. We highlight how a fine-tuned assembly line of bricks (H3.3 and CENP-A) and architects (HIRA, HJURP, and DAXX) is key in adaptation to developmental and pathological changes. An example of this conceptual advance is the exquisite sensitivity displayed by p53-null tumor cells to modulation of HJURP, the histone chaperone for CENP-A (CenH3 variant). We discuss how these findings open avenues for novel therapeutic paradigms in cancer care.

Chromatin plasticity: A versatile landscape that underlies cell fate and identity

“…he genome of eukaryotic cells is organized into chromatin, a nuclear complex comprising DNA, RNA, and associated proteins (1,2). Chromatin organization displays hierarchical levels ranging from the basic repeated unit, the nucleosome, to higher-level structures (Fig.…”

A versatile mouse model of epitope-tagged histone H3.3 to study epigenome dynamics

“…H3.3 is a conserved variant histone distinct from the canonical histone H3 (H3.1 and H3.2). Although it differs only in four or five amino acids from the canonical H3, H3.3 has an activity and mode of action different from H3.1 and H3.2 (1)(2)(3). Unlike the canonical histone H3, which is synthesized and deposited into nucleosomes during DNA replication, H3.3 is expressed throughout cell cycle and is incorporated into chromatin along with transcription.…”

Imaging the response to DNA damage in heterochromatin domains reveals core principles of heterochromatin maintenance

“…4b). Regarding H3.3 histone chaperones, both HIRA (Histone Regulator A) and DAXX (Death Domain Associated Protein) can drive H3.3 deposition (reviewed in 65 ). HIRA deposits H3.3 within transcribed euchromatin in mammalian cells 66,67 and in UVCdamaged chromatin in human cells 50 , while DAXX promotes H3.3 enrichment at repeated sequences including pericentric heterochromatin 66,68,69 .…”