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X-chromosome hyperactivation in mammals via nonlinear relationships between chromatin states and transcription

Abstract

Dosage compensation in mammals occurs at two levels. In addition to balancing X-chromosome dosage between males and females via X inactivation, mammals also balance dosage of Xs and autosomes. It has been proposed that X-autosome equalization occurs by upregulation of Xa (active X). To investigate mechanism, we perform allele-specific ChIP-seq for chromatin epitopes and analyze RNA-seq data. The hypertranscribed Xa demonstrates enrichment of active chromatin marks relative to autosomes. We derive predictive models for relationships among Pol II occupancy, active mark densities and gene expression, and we suggest that Xa upregulation involves increased transcription initiation and elongation. Enrichment of active marks on Xa does not scale proportionally with transcription output, a disparity explained by nonlinear quantitative dependencies among active histone marks, Pol II occupancy and transcription. Notably, the trend of nonlinear upregulation also occurs on autosomes. Thus, Xa upregulation involves combined increases of active histone marks and Pol II occupancy, without invoking X-specific dependencies between chromatin states and transcription.

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Figure 1: Allele-specific ChIP-seq.
Figure 2: Distributions of coverage densities for Pol II and active histone modifications on X chromosome and autosomes.
Figure 3: Relationships between levels of gene expression, Pol II and active histone modifications.
Figure 4: Autosomal relationships between active histone modifications, Pol II and expression are predictive of X-linked gene expression.

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Gene Expression Omnibus

Sequence Read Archive

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Acknowledgements

We are thankful to members of Lee laboratory for valuable discussions, to Y. Jeon for F1 mus/cast female MEFs and to B. Chapman, M. Borowsky and T. Ohsumi of the Bioinformatics Core Facility (Department of Molecular Biology, Massachusetts General Hospital (MGH)) for their suggestions for ChIP-Seq analysis. This work was supported by the MGH ECOR Medical Discovery Fund (E.Y.), the Deutsche Forschungsgemeinschaft (S.F.P.) and the US National Institutes of Health (RO1-GM090278, J.T.L.). J.T.L. is an investigator of the Howard Hughes Medical Institute.

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E.Y. and J.T.L. designed the research; E.Y. and S.F.P. conducted ChIP-seq experiments; R.I.S. performed the bioinformatics analysis; S.F.P. designed the allele-specific ChIP-seq strategy and performed allele-specific alignments; E.Y., R.I.S., S.F.P., and J.T.L. analyzed the data; and E.Y., R.I.S., and J.T.L. wrote the paper.

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Correspondence to Jeannie T Lee.

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The authors declare no competing financial interests.

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Yildirim, E., Sadreyev, R., Pinter, S. et al. X-chromosome hyperactivation in mammals via nonlinear relationships between chromatin states and transcription. Nat Struct Mol Biol 19, 56–61 (2012). https://doi.org/10.1038/nsmb.2195

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