Local compartment changes and regulatory landscape alterations in histone H1-depleted cells.

Geert Geeven,Marit W Vermunt,Boris A Bartholdy,Seung-Min Yang,Arthur I Skoultchi,Wesley D Gifford,Patrick J Wijchers,Yun Zhu,Byung Ju Kim,Marjon J A M Verstegen,Todd S Macfarlan,John A Stamatoyannopoulos,Hugo Pinto,Wouter De Laat,Menno P Creyghton,Samuel L Pfaff

doi:10.1186/s13059-015-0857-0

Abstract

BackgroundLinker histone H1 is a core chromatin component that binds to nucleosome core particles and the linker DNA between nucleosomes. It has been implicated in chromatin compaction and gene regulation and is anticipated to play a role in higher-order genome structure. Here we have used a combination of genome-wide approaches including DNA methylation, histone modification and DNase I hypersensitivity profiling as well as Hi-C to investigate the impact of reduced cellular levels of histone H1 in embryonic stem cells on chromatin folding and function.ResultsWe find that depletion of histone H1 changes the epigenetic signature of thousands of potential regulatory sites across the genome. Many of them show cooperative loss or gain of multiple chromatin marks. Epigenetic alterations cluster to gene-dense topologically associating domains (TADs) that already showed a high density of corresponding chromatin features. Genome organization at the three-dimensional level is largely intact, but we find changes in the structural segmentation of chromosomes specifically for the epigenetically most modified TADs.ConclusionsOur data show that cells require normal histone H1 levels to expose their proper regulatory landscape. Reducing the levels of histone H1 results in massive epigenetic changes and altered topological organization particularly at the most active chromosomal domains. Changes in TAD configuration coincide with epigenetic landscape changes but not with transcriptional output changes, supporting the emerging concept that transcriptional control and nuclear positioning of TADs are not causally related but independently controlled by the locally associated trans-acting factors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0857-0) contains supplementary material, which is available to authorized users.

Highlights

Linker histone H1 is a core chromatin component that binds to nucleosome core particles and the linker DNA between nucleosomes
To further delineate the clustered distribution, we investigated the density of differentially methylated sites in topologically associating domains (TADs)
Embryonic stem (ES) cell-specific interactions among binding sites of Oct4, Nanog, and Klf4 remain present in mouse ES cells upon depletion of H1 in triple knock-out (TKO) cells. c Plot comparing the distribution of Hi-C interactions versus genomic distance for three different Hi-C maps

Summary

Introduction

Linker histone H1 is a core chromatin component that binds to nucleosome core particles and the linker DNA between nucleosomes. Embryonic stem (ES) cells derived from H1c, H1d, H1e null embryos are viable and exhibit a 50 % reduction in H1:core histone stoichiometry They show a decrease in the average spacing between nucleosome core particles of about 15 bp, from ~189 bp in normal ES cells to ~174 bp in the triple H1 knock-out (TKO) ES cells [12]. CTCF is a central factor in setting up local chromatin loops and defining structural domains across mammalian chromosomes [15, 16] This suggests that histone H1 may have an important function in shaping higher order genome structures in vivo, either directly through its capacity to compact DNA or indirectly by controlling the DNA accessibility of chromatin architectural proteins

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Results

Conclusion