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Epigenetic stability in the adult mouse cortex under conditions of pharmacologically induced histone acetylation

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Abstract

Histone acetylation is considered a major epigenetic process that affects brain development and synaptic plasticity, as well as learning and memory. The transcriptional effectors and morphological changes responsible for plasticity as a result of long-term modifications to histone acetylation are not fully understood. To this end, we pharmacologically inhibited histone deacetylation using Trichostatin A in adult (6-month-old) mice and found significant increases in the levels of the acetylated histone marks H3Lys9, H3Lys14 and H4Lys12. High-resolution transcriptome analysis of diverse brain regions uncovered few differences in gene expression between treated and control animals, none of which were plasticity related. Instead, after increased histone acetylation, we detected a large number of novel transcriptionally active regions, which correspond to long non-coding RNAs (lncRNAs). We also surprisingly found no significant changes in dendritic spine plasticity in layers 1 and 2/3 of the visual cortex using long-term in vivo two-photon imaging. Our results indicate that chronic pharmacologically induced histone acetylation can be decoupled from gene expression and instead, may potentially exert a post-transcriptional effect through the differential production of lncRNAs.

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Acknowledgments

We would like to thank Steven Reilly for his assistance with the RNA-seq pipeline and data analysis and Dr. Andy Shih for his assistance with teaching the cortical thinning technique. The authors acknowledge the technical assistance of Mariamma Pappy and Shawna Rodriguez. We also thank members of the Rakic lab for critical comments on the manuscript. J.B. is supported by a Natural Sciences and Engineering Research Council of Canada Postgraduate Fellowship 403855-2011 and the Department of Psychology at Yale University. This work was supported by National Institutes of Health Grants DA02399 (to P. R and A. E. A), and the Kavli Institute for Neuroscience at Yale University. We thank Christopher Castaldi, David Harrison, and Kaya Bilguvar for assistance with RNAseq at the Yale Center for Genome Analysis. The Yale University Biomedical High Performance Computing Center is supported by NIH Grant RR19895.

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  1. Jamie Benoit

    Present address: Department of Brain and Cognitive Sciences, Picower Institute of Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

Authors and Affiliations

  1. Department of Psychology, Yale University, New Haven, CT, 06520, USA

    Jamie Benoit

  2. Department of Neurobiology, Yale University School of Medicine, New Haven, CT, 06520, USA

    Albert Ayoub & Pasko Rakic

  3. Kavli Institute for Neuroscience Yale University, New Haven, CT, 06520, USA

    Pasko Rakic

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Correspondence to Jamie Benoit.

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Benoit, J., Ayoub, A. & Rakic, P. Epigenetic stability in the adult mouse cortex under conditions of pharmacologically induced histone acetylation. Brain Struct Funct 221, 3963–3978 (2016). https://doi.org/10.1007/s00429-015-1138-0

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