Abstract
Nucleosome occupancy is critically important in regulating access to the eukaryotic genome. Few studies in human cells have measured genome-wide nucleosome distributions at high temporal resolution during a response to a common stimulus. We measured nucleosome distributions at high temporal resolution following Kaposi's-sarcoma-associated herpesvirus (KSHV) reactivation using our newly developed mTSS-seq technology, which maps nucleosome distribution at the transcription start sites (TSS) of all human genes. Nucleosomes underwent widespread changes in organization 24 hours after KSHV reactivation and returned to their basal nucleosomal architecture 48 hours after KSHV reactivation. The widespread changes consisted of an indiscriminate remodeling event resulting in the loss of nucleosome rotational phasing signals. Additionally, one in six TSSs in the human genome possessed nucleosomes that are translationally remodeled. 72% of the loci with translationally remodeled nucleosomes have nucleosomes that moved to positions encoded by the underlying DNA sequence. Finally we demonstrated that these widespread alterations in nucleosomal architecture potentiated regulatory factor binding. These descriptions of nucleosomal architecture changes provide a new framework for understanding the role of chromatin in the genomic response, and have allowed us to propose a hierarchical model for chromatin-based regulation of genome response.
Highlights
In eukaryotic cells, DNA is packed into chromatin
Using mTSS-seq, we show that Kaposi’s-sarcoma-associated herpesvirus (KSHV) reactivation-induced nucleosome remodeling is apparently an indiscriminate event affecting a majority of nucleosomes at all transcription start sites (TSS)
An A/T-containing dinucleotide periodicity was retained at 0, 6, 12, and 48 hour time points and was lost at the 24 hour time point (Figure 2B). This analysis argues for a majority of nucleosomal-sized fragments shifting in either direction in an indiscriminate, widespread remodeling event. These results suggest that there is a loss of nucleosome rotational phasing signals after KSHV reactivation
Summary
The fundamental subunit of chromatin is the nucleosome: approximately 150 base pairs (bp) of DNA wrapped around a histone octamer core [1, 2]. It has been proposed that nucleosomes play a role in genome response by regulating access to underlying DNA sequence [3]. The position, density, and occupancy of nucleosomes are determined by factors acting in cis, DNA sequence patterns, and those in trans, protein complexes. It is clear that cis-acting DNA sequence patterns influence nucleosome distributions. Two approaches have been taken to classify DNA sequences as nucleosome-forming or nucleosomeinhibitory. An alternate approach has been to identify more cryptic and sophisticated genetically-encoded signals using models that discriminate between nucleosome-forming and nucleosome-inhibitory DNA sequences [6, 7]. The precise genetically-encoded signals and the extent to which they direct nucleosome position is still a matter of considerable debate [8]
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