Coordinated neuron-specific splicing events restrict nucleosome engagement of the LSD1 histone demethylase complex
Robert S. Porter,
Sojin An,
Maria C. Gavilan,
Masayoshi Nagai,
Yumie Murata-Nakamura,
Bo Zhou,
Katherine M. Bonefas,
Olivier Dionne,
Jeru Manoj Manuel,
Joannie St-Germain,
Suzanne Gascon,
Jacqueline Kim,
Liam Browning,
Benoit Laurent,
Uhn-Soo Cho,
Shigeki Iwase
Affiliations
Robert S. Porter
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Sojin An
Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Maria C. Gavilan
Genetics and Genomics Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA
Masayoshi Nagai
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Yumie Murata-Nakamura
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Bo Zhou
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Katherine M. Bonefas
Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Olivier Dionne
Research Center on Aging, Centre Intégré Universitaire de Santé et Services Sociaux de l’Estrie-Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
Jeru Manoj Manuel
Research Center on Aging, Centre Intégré Universitaire de Santé et Services Sociaux de l’Estrie-Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
Joannie St-Germain
Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
Suzanne Gascon
Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Research Center on Aging, Centre Intégré Universitaire de Santé et Services Sociaux de l’Estrie-Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada
Jacqueline Kim
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Liam Browning
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Benoit Laurent
Research Center on Aging, Centre Intégré Universitaire de Santé et Services Sociaux de l’Estrie-Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
Uhn-Soo Cho
Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Shigeki Iwase
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA; Corresponding author
Summary: Chromatin regulatory proteins are expressed broadly and assumed to exert the same intrinsic function across cell types. Here, we report that 14 chromatin regulators undergo evolutionary-conserved neuron-specific splicing events involving microexons. Among them are two components of a histone demethylase complex: LSD1 H3K4 demethylase and the H3K4me0-reader PHF21A. We found that neuronal LSD1 splicing reduces the enzymes’ affinity to the nucleosome. Meanwhile, neuronal PHF21A splicing significantly attenuates histone H3 binding and further ablates the DNA-binding function exerted by an AT-hook motif. Furthermore, in vitro reconstitution of the canonical and neuronal PHF21A-LSD1 complexes, combined with in vivo methylation mapping, identified the neuronal complex as a hypomorphic H3K4 demethylating machinery. The neuronal PHF21A, albeit with its weaker nucleosome binding, is necessary for normal gene expression and the H3K4 landscape in the developing brain. Thus, ubiquitously expressed chromatin regulatory complexes can exert neuron-specific functions via alternative splicing of their subunits.
