Abstract
The fundamental molecular determinants by which ATP-dependent chromatin remodelers organize nucleosomes across eukaryotic genomes remain largely elusive. Here, chromatin reconstitutions on physiological, whole-genome templates reveal how remodelers read and translate genomic information into nucleosome positions. Using the yeast genome and the multi-subunit INO80 remodeler as a paradigm, we identify DNA shape/mechanics encoded signature motifs as sufficient for nucleosome positioning and distinct from known DNA sequence preferences of histones. INO80 processes such information through an allosteric interplay between its core- and Arp8-modules that probes mechanical properties of nucleosomal and linker DNA. At promoters, INO80 integrates this readout of DNA shape/mechanics with a readout of co-evolved sequence motifs via interaction with general regulatory factors bound to these motifs. Our findings establish a molecular mechanism for robust and yet adjustable +1 nucleosome positioning and, more generally, remodelers as information processing hubs that enable active organization and allosteric regulation of the first level of chromatin.
Highlights
The fundamental molecular determinants by which ATP-dependent chromatin remodelers organize nucleosomes across eukaryotic genomes remain largely elusive
As pronounced +1 nucleosome positioning activity was observed for recombinant as for endogenous INO80 (Fig. 2b, left), we concluded that no yeast-specific posttranslational modifications (PTMs) of INO80 were required and no co-purified yeast contaminant was responsible
Similar but asymmetrically distorted shape profiles were seen for nucleosomes reconstituted at positions close to in vivo +1 nucleosome positions and oriented relative to the direction of transcription (Fig. 4c). This defined orientation led to asymmetrical profiles and showed that such pronounced DNA shape signals are present in +1 nucleosome regions at gene promoters and strongly suggested that we identified the DNA-encoded signal for INO80-mediated +1 nucleosome positioning
Summary
The fundamental molecular determinants by which ATP-dependent chromatin remodelers organize nucleosomes across eukaryotic genomes remain largely elusive. A molecular mechanism that consistently places a nucleosome at a particular genome position across a cell population must select this position against competing positions This selection may be based on genetic information encoded within DNA sequence or on epigenetic information like histone modifications and variants or other chromatin-associated factors. One mechanism, designated as a genomic code for nucleosome positioning, relies on the intrinsic preference of nucleosomes to assemble on DNA sequences that favor wrapping around the histone octamer[14,15] DNA sequence is read somewhere else, and the resulting positioning information is relayed by alignment mechanisms that position nucleosomes relative to barriers and other nucleosomes In the latter case, the DNA sequence bound by the histone octamer would define, but not directly determine, the genomic position of a nucleosome
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