Abstract
During eukaryotic evolution, genome size has increased disproportionately to nuclear volume, necessitating greater degrees of chromatin compaction in higher eukaryotes, which have evolved several mechanisms for genome compaction. However, it is unknown whether histones themselves have evolved to regulate chromatin compaction. Analysis of histone sequences from 160 eukaryotes revealed that the H2A N-terminus has systematically acquired arginines as genomes expanded. Insertion of arginines into their evolutionarily conserved position in H2A of a small-genome organism increased linear compaction by as much as 40%, while their absence markedly diminished compaction in cells with large genomes. This effect was recapitulated in vitro with nucleosomal arrays using unmodified histones, indicating that the H2A N-terminus directly modulates the chromatin fiber likely through intra- and inter-nucleosomal arginine-DNA contacts to enable tighter nucleosomal packing. Our findings reveal a novel evolutionary mechanism for regulation of chromatin compaction and may explain the frequent mutations of the H2A N-terminus in cancer.
Highlights
Genome size, defined as the haploid DNA content of a cell, has increased as eukaryotes evolved from single-cell species to more complex, multicellular organisms
Increases in genome size are associated with phylogenetic evolution from protozoa to fungi to more complex plants and animals, we present genetic and molecular evidence from the budding yeast and human cells as well as in vitro biochemical data to demonstrate that the evolutionary changes in H2A directly regulate chromatin compaction in vivo and in vitro with consequences for the nuclear volume
Our findings suggest that the reported mutations in the histone H2A N-terminal domain (NTD) may contribute to the altered chromatin compaction that is commonly observed in cancer cells (Zink et al, 2004)
Summary
Genome size, defined as the haploid DNA content of a cell, has increased as eukaryotes evolved from single-cell species to more complex, multicellular organisms. Within the same evolutionary timeframe, nuclear volume has increased but at a slower rate than genome size expansion (Maul and Deaven, 1977; Olmo, 1982). The genome is organized into chromatin by the repeating nucleosomal structure (Luger et al, 1997). The nucleosomes stack and fold into higher order structures, serving to systematically compact the genome (Lieberman-Aiden et al, 2009; Duan et al, 2010) and to regulate molecular processes that are based on DNA (Celeste et al, 2002; Vogelauer et al, 2002; Fischle et al, 2005; Kouzarides, 2007; Fussner et al, 2011)
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