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

doi:10.1016/j.celrep.2024.115213

Coordinated neuron-specific splicing events restrict nucleosome engagement of the LSD1 histone demethylase complex

Cell Rep. 2025 Jan 15;44(1):115213. doi: 10.1016/j.celrep.2024.115213. Online ahead of print.

Authors

Robert S Porter¹, Sojin An², Maria C Gavilan³, Masayoshi Nagai¹, Yumie Murata-Nakamura¹, Bo Zhou¹, Katherine M Bonefas⁴, Olivier Dionne⁵, Jeru Manoj Manuel⁵, Joannie St-Germain⁶, Suzanne Gascon⁷, Jacqueline Kim¹, Liam Browning¹, Benoit Laurent⁵, Uhn-Soo Cho², Shigeki Iwase⁸

Affiliations

¹ Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
² Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
³ 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.
⁴ Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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. Electronic address: [email protected].

PMID: 39817906
DOI: 10.1016/j.celrep.2024.115213

Abstract

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.

Keywords: CP: Molecular biology; CP: Neuroscience; alternative splicing; cellular differentiation; chromatin regulation; genetics of autism spectrum disorder; methyl-histone regulation; neurodevelopment.