Abstract
The packaging and organization of genomic DNA into chromatin represents an additional regulatory layer of gene expression, with specific nucleosome positions that restrict the accessibility of regulatory DNA elements. The mechanisms that position nucleosomes in vivo are thought to depend on the biophysical properties of the histones, sequence patterns, like phased di-nucleotide repeats and the architecture of the histone octamer that folds DNA in 1.65 tight turns. Comparative studies of human and P. falciparum histones reveal that the latter have a strongly reduced ability to recognize internal sequence dependent nucleosome positioning signals. In contrast, the nucleosomes are positioned by AT-repeat sequences flanking nucleosomes in vivo and in vitro. Further, the strong sequence variations in the plasmodium histones, compared to other mammalian histones, do not present adaptations to its AT-rich genome. Human and parasite histones bind with higher affinity to GC-rich DNA and with lower affinity to AT-rich DNA. However, the plasmodium nucleosomes are overall less stable, with increased temperature induced mobility, decreased salt stability of the histones H2A and H2B and considerable reduced binding affinity to GC-rich DNA, as compared with the human nucleosomes. In addition, we show that plasmodium histone octamers form the shortest known nucleosome repeat length (155bp) in vitro and in vivo. Our data suggest that the biochemical properties of the parasite histones are distinct from the typical characteristics of other eukaryotic histones and these properties reflect the increased accessibility of the P. falciparum genome.
Highlights
The human malaria parasite, Plasmodium falciparum, yearly responsible for an estimated 600,000 deaths (WHO Report 2014), has the AT-richest genome sequenced to date
We determined the biochemical properties of plasmodium histones and show that they are distinct from
The Biochemical Properties of P. falciparum Nucleosomes Determine Its Open Chromatin Architecture funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Summary
The human malaria parasite, Plasmodium falciparum, yearly responsible for an estimated 600,000 deaths (WHO Report 2014), has the AT-richest genome sequenced to date. At least 60% of the genome is transcriptionally active during erythrocytic development with gene expression being activated in form of a cascade and tightly regulated during developmental stage transition [2,3]. The plasmodium forms nucleosomes, possesses chromatin modifiers, chromatin remodeling activities and potentially active DNA methyltransferases [4]. H3 homo-dimerizes using the C-terminal ends and heterodimerizes with H4 to form a H3–H4 tetramer [6]. Histone dimers composed either of H2A and H2B, or H3 and H4 organize each 30bp of DNA. Two H3-H4 dimers bind to the central 60bp of nucleosomal DNA and each H2A-H2B dimer organizes 30bp towards the end of the particle [5]. Almost 400 direct and indirect histone-DNA interactions render the nucleosome one of the most stable protein-DNA complexes under physiological conditions [5]
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