High Nucleosome Occupancy Is Encoded at Human Regulatory Sequences

Desiree Tillo,Jonathan Widom,Yvonne Fondufe-Mittendorf,Irene K Moore,Andrea J Gossett,Jason D Lieb,Noam Kaplan,Yair Field,Timothy R Hughes,Eran Segal,Sridhar Hannenhalli

doi:10.1371/journal.pone.0009129

Desiree Tillo, Jonathan Widom + Show 9 more

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https://doi.org/10.1371/journal.pone.0009129

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Abstract

Active eukaryotic regulatory sites are characterized by open chromatin, and yeast promoters and transcription factor binding sites (TFBSs) typically have low intrinsic nucleosome occupancy. Here, we show that in contrast to yeast, DNA at human promoters, enhancers, and TFBSs generally encodes high intrinsic nucleosome occupancy. In most cases we examined, these elements also have high experimentally measured nucleosome occupancy in vivo. These regions typically have high G+C content, which correlates positively with intrinsic nucleosome occupancy, and are depleted for nucleosome-excluding poly-A sequences. We propose that high nucleosome preference is directly encoded at regulatory sequences in the human genome to restrict access to regulatory information that will ultimately be utilized in only a subset of differentiated cells.

Highlights

Active regulatory sequences are generally thought to be depleted of nucleosomes, presumably due to steric constraints between nucleosomes and most other DNA-binding proteins, such as transcription factors (TFs)
We show that in vivo occupancy positively and significantly correlates with intrinsic nucleosome occupancy, indicating that intrinsic histone-DNA sequence preferences play a role in dictating nucleosome arrangement in vivo
Based on the major role that intrinsic histone-DNA preferences play in determining in vivo nucleosome occupancy in yeast [1,2], we speculated that DNA sequence may influence human nucleosome occupancy

Summary

Introduction

Active regulatory sequences are generally thought to be depleted of nucleosomes, presumably due to steric constraints between nucleosomes and most other DNA-binding proteins, such as transcription factors (TFs). Regulatory regions in human are typically celltype-specific [3], suggesting that the chromatin state may not be encoded directly in the DNA sequence, which does not vary between cell types. Unlike yeast, regulatory sequences in human have higher than average intrinsic nucleosome occupancy, suggesting that restricted access to cell-type specific regulatory DNA is encoded directly in the genomes of complex organisms. We show that this difference is associated with local variations in base composition (G+C content), which correlates with both nucleosome occupancy and regulatory function, as well as the probability of rigid, nucleosome-excluding polyA-like sequences [6,7]. We suggest possible implications of these overlapping signals in determining chromatin structure and mechanisms of gene regulation

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