Abstract
The dynamic architecture of chromatin is vital for proper cellular function, and is maintained by the concerted action of numerous nuclear proteins, including that of the linker histone H1 variants, the most abundant family of nucleosome-binding proteins. Here we show that the nuclear protein HP1BP3 is widely expressed in most vertebrate tissues and is evolutionarily and structurally related to the H1 family. HP1BP3 contains three globular domains and a highly positively charged C-terminal domain, resembling similar domains in H1. Fluorescence recovery after photobleaching (FRAP) studies indicate that like H1, binding of HP1BP3 to chromatin depends on both its C and N terminal regions and is affected by the cell cycle and post translational modifications. HP1BP3 contains functional motifs not found in H1 histones, including an acidic stretch and a consensus HP1-binding motif. Transcriptional profiling of HeLa cells lacking HP1BP3 showed altered expression of 383 genes, suggesting a role for HP1BP3 in modulation of gene expression. Significantly, Hp1bp3−/− mice present a dramatic phenotype with 60% of pups dying within 24 h of birth and the surviving animals exhibiting a lifelong 20% growth retardation. We suggest that HP1BP3 is a ubiquitous histone H1 like nuclear protein with distinct and non-redundant functions necessary for survival and growth.
Highlights
Organization of the vast genomes of eukaryotic cells in the confines of the nucleus, while still allowing tightly regulated access to transcription factors demands a complex system of dynamic compaction
While the sequence of the C-terminal domain (CTD) is not similar to that of any H1 subtype, the amino acid composition is strikingly close to that of the CTDs of the gonadal subtypes H1.8 (formerly H1foo; see [36] for new nomenclature) and H1.6. This layout of globular domains flanked by an unstructured N-terminal domain (NTD) and a very basic CTD is highly reminiscent of the tri-partite linker histone structure (Figure 1B)
In this study we show that HP1BP3 evolved from the linker histone H1 gene family and that it retains many of the family’s structural and functional characteristics
Summary
Organization of the vast genomes of eukaryotic cells in the confines of the nucleus, while still allowing tightly regulated access to transcription factors demands a complex system of dynamic compaction. This is achieved by the packaging of DNA into chromatin. The subtypes differ from each other in a variety of aspects, including chromatin dynamics [9,10,11,12], cell type and tissue-specificity [13,14,15,16], developmental regulation [17,18], evolutionary stability [19] and posttranslational modifications [9,10,11,20]. In spite of all of these differences, knockout of single somatic H1 subtypes in mice does not lead to any obvious phenotype [22,23,24]
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