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Abstract

We found that a neuron-specific isoform of LSD1, LSD1n, which results from an alternative splicing event, acquires a new substrate specificity, targeting histone H4 Lys20 methylation, both in vitro and in vivo. Selective genetic ablation of LSD1n led to deficits in spatial learning and memory, revealing the functional importance of LSD1n in neuronal activity–regulated transcription that is necessary for long-term memory formation. LSD1n occupied neuronal gene enhancers, promoters and transcribed coding regions, and was required for transcription initiation and elongation steps in response to neuronal activity, indicating the crucial role of H4K20 methylation in coordinating gene transcription with neuronal function. Our results indicate that this alternative splicing of LSD1 in neurons, which was associated with altered substrate specificity, serves as a mechanism acquired by neurons to achieve more precise control of gene expression in the complex processes underlying learning and memory.

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  • 17 August 2015

    In the version of this article initially published online, author Cagdas Tazearslan's name was misspelled Tazearsalan. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank J. Chen (University of California San Diego, UCSD) for pLNL vector for LSD1n gene targeting, and S. Wu and M. Capecchi (University of Utah) for pCAG-LSL vector for generation of Lsd1 transgenic mice. We thank J. Zhao and E. Kothari (UCSD transgenic core) for generating knockout and transgenic mice, S. Roberts (The Scripps Research Institute Mouse Behavioral Core) for behavioral assessment, H. Karten (UCSD) for brain anatomy analysis, M. Ghassemian (UCSD) for MALDI-TOF mass spectrometry analysis, A. Gamliel, R. McEvilly, I. Garcia-Bassets, B. Bloodgood and C.K. Glass (UCSD) for discussion, comments, suggestions and critical reading of the manuscript, R. Pardee for proofreading of the manuscript, and J. Hightower for help with figure preparation. J.W. receives funding from a US National Institutes of Health T32 Postdoctoral Fellowship. F.T. was supported by grants from the Roche Extending Innovation Network Program. W.L. was supported by a Department of Defense postdoctoral fellowship. S.L.P. (Benjamin H. Lewis Chair in Neuroscience) and M.G.R. receive funding from the Howard Hughes Medical Institute. This research was supported by grants from the National Institute of Neurological Disorders and Stroke (R37NS5037116) to S.L.P. and by grants from the US National Institutes of Health and the National Cancer Institute (DK018477, NS034934, DK039949, HL065445 and CA173903) to M.G.R. Y.S. received funding from the US National Institutes of Health and the National Institute of General Medical Sciences (R01GM104459-01).

Author information

Author notes

    • Jianxun Wang
    • , Francesca Telese
    •  & Yuliang Tan

    These authors contributed equally to this work.

Affiliations

  1. Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, USA.

    • Jianxun Wang
    • , Francesca Telese
    • , Yuliang Tan
    • , Wenbo Li
    • , Chunyu Jin
    • , Harihar Basnet
    • , Qi Ma
    • , Daria Merkurjev
    • , Xiaoyan Zhu
    • , Zhijie Liu
    • , Jie Zhang
    • , Kenny Ohgi
    • , Havilah Taylor
    •  & Michael G Rosenfeld
  2. College of Basic Medicine, Beijing University of Chinese Medicine, Beijing, China.

    • Jianxun Wang
    •  & Xin He
  3. Department of Genetics and Medicine, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, USA.

    • Ryan R White
    • , Cagdas Tazearslan
    •  & Yousin Suh
  4. National Institute of Child Health and Human Development, US National Institutes of Health, Bethesda, Maryland, USA.

    • Todd S Macfarlan
  5. Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA.

    • Samuel L Pfaff

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Contributions

J.W., F.T., Y.T. and M.G.R. conceived the project. J.W. performed the biochemical characterization of LSD1n, with assistance from C.J., X.H., H.B., Z.L. and X.Z. J.W. generated the murine genetic models, with assistance from H.T. F.T. performed all of the analyses using primary cortical neuronal cultures and helped to coordinate all of the behavioral studies. Y.T. performed GRO-seq experiments and bioinformatics analyses, with assistance from D.M. and Q.M. W.L. performed GRO-seq experiments, and K.O. and J.Z. performed deep-sequencing experiments. R.R.W., C.T. and Y.S. performed gene expression analysis in young and old mice. T.S.M. and S.L.P. performed gene expression analysis in embryonic stem cells.J.W., F.T., Y.T. and M.G.R. wrote the manuscript. All of the authors reviewed and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jianxun Wang or Francesca Telese or Michael G Rosenfeld.

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https://doi.org/10.1038/nn.4069

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