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Multilayered chromatin analysis reveals E2f, Smad and Zfx as transcriptional regulators of histones

Nature Structural & Molecular Biology volume 20, pages 119–126 (2013)Cite this article

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Abstract

Histones, the building blocks of eukaryotic chromatin, are essential for genome packaging, function and regulation. However, little is known about their transcriptional regulation. Here we conducted a comprehensive computational analysis, based on chromatin immunoprecipitation–sequencing and −microarray analysis (ChIP-seq and ChIP-chip) data of over 50 transcription factors and histone modifications in mouse embryonic stem cells. Enrichment scores supported by gene expression data from gene knockout studies identified E2f1 and E2f4 as master regulators of histone genes, CTCF and Zfx as repressors of core and linker histones, respectively, and Smad1, Smad2, YY1 and Ep300 as restricted or cell type–specific regulators. We propose that histone gene regulation is substantially more complex than previously thought, and that a combination of factors orchestrate histone gene regulation, from strict synchronization with S phase to targeted regulation of specific histone subtypes.

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Figure 1: Multifactorial regulation of histone genes.
Figure 2: Enrichment analysis of multiple TFs.
Figure 3: E2f1 and E2f4 are enriched in all histone subtypes.
Figure 4: Histone genes are a main target of Smad proteins.
Figure 5: Zfx negatively regulates linker histones.
Figure 6: CTCF and YY1 binding to histone genes.
Figure 7: Pair-wise distance between TF binding signatures reveals distinct transcriptional regulation for different histones.

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Acknowledgements

We thank L. Carmel and Y. Aaronson for help with statistical analyses, and H. Margalit and O. Rando for critical comments. This work was supported by the Israel Science Foundation, the Abisch Frenkel Foundation, the Israel Cancer Research Foundation and the European Research Council (ERC-281781).

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Authors and Affiliations

  1. Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel

    David Gokhman, Ilana Livyatan, Badi Sri Sailaja, Shai Melcer & Eran Meshorer

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  1. David Gokhman
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  2. Ilana Livyatan
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D.G. and E.M. conceived the idea; D.G. and I.L. analyzed the data; B.S.S. and S.M. performed the experiments; D.G. and E.M. wrote the paper.

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Correspondence to Eran Meshorer.

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Gokhman, D., Livyatan, I., Sailaja, B. et al. Multilayered chromatin analysis reveals E2f, Smad and Zfx as transcriptional regulators of histones. Nat Struct Mol Biol 20, 119–126 (2013). https://doi.org/10.1038/nsmb.2448

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