title: LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control.
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.
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, USA.|College of Basic Medicine, Beijing University of Chinese Medicine, Beijing, China.
authors.forename: Jianxun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Telese
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Yuliang
authors.identifier: http://orcid.org/0000-0002-3146-8218
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Li
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Jin
authors.affiliation: College of Basic Medicine, Beijing University of Chinese Medicine, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Harihar
authors.initials: H
authors.lastname: Basnet
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Merkurjev
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Kenny
authors.initials: K
authors.lastname: Ohgi
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Havilah
authors.initials: H
authors.lastname: Taylor
authors.affiliation: Department of Genetics and Medicine, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Ryan R
authors.initials: RR
authors.lastname: White
authors.affiliation: Department of Genetics and Medicine, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Cagdas
authors.initials: C
authors.lastname: Tazearslan
authors.affiliation: Department of Genetics and Medicine, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Yousin
authors.initials: Y
authors.lastname: Suh
authors.affiliation: National Institute of Child Health and Human Development, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Todd S
authors.initials: TS
authors.lastname: Macfarlan
authors.affiliation: Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Pfaff
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism*; D006657:Histones / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D057567:Memory, Long-Term / Q000502:physiology*; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D006657:Histones; D056466:Histone Demethylases; C504076:KDM1a protein, mouse