Coordinated neuron-specific splicing events restrict nucleosome engagement of the LSD1 histone demethylase complex
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 histon...
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| Language: | English |
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Elsevier
2025-01-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472401564X |
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| author | 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 |
| author_facet | 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 |
| author_sort | Robert S. Porter |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-7c98505733d74ba2bf5473790ed9d16a |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-7c98505733d74ba2bf5473790ed9d16a2025-01-16T04:28:35ZengElsevierCell Reports2211-12472025-01-01441115213Coordinated neuron-specific splicing events restrict nucleosome engagement of the LSD1 histone demethylase complexRobert S. Porter0Sojin An1Maria C. Gavilan2Masayoshi Nagai3Yumie Murata-Nakamura4Bo Zhou5Katherine M. Bonefas6Olivier Dionne7Jeru Manoj Manuel8Joannie St-Germain9Suzanne Gascon10Jacqueline Kim11Liam Browning12Benoit Laurent13Uhn-Soo Cho14Shigeki Iwase15Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USAGenetics and Genomics Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USADepartment of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USANeuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USAResearch 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, CanadaResearch 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, CanadaNeuroscience 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, CanadaNeuroscience 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, CanadaDepartment of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USAResearch 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, CanadaDepartment of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S221112472401564XCP: Molecular biologyCP: Neuroscience |
| spellingShingle | 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 Coordinated neuron-specific splicing events restrict nucleosome engagement of the LSD1 histone demethylase complex Cell Reports CP: Molecular biology CP: Neuroscience |
| title | Coordinated neuron-specific splicing events restrict nucleosome engagement of the LSD1 histone demethylase complex |
| title_full | Coordinated neuron-specific splicing events restrict nucleosome engagement of the LSD1 histone demethylase complex |
| title_fullStr | Coordinated neuron-specific splicing events restrict nucleosome engagement of the LSD1 histone demethylase complex |
| title_full_unstemmed | Coordinated neuron-specific splicing events restrict nucleosome engagement of the LSD1 histone demethylase complex |
| title_short | Coordinated neuron-specific splicing events restrict nucleosome engagement of the LSD1 histone demethylase complex |
| title_sort | coordinated neuron specific splicing events restrict nucleosome engagement of the lsd1 histone demethylase complex |
| topic | CP: Molecular biology CP: Neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S221112472401564X |
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