Division of labor among H3K4 methyltransferases defines distinct facets of homeostatic plasticity
Takao Tsukahara,
Saini Kethireddy,
Katherine M. Bonefas,
Alex Chen,
Brendan L.M. Sutton,
Kenjiro Bandow,
Yali Dou,
Shigeki Iwase,
Michael A. Sutton
Affiliations
Takao Tsukahara
Michigan Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Meikai University School of Dentistry, Department of Oral Biology and Tissue Engineering, Division of Biochemistry, Sakado, Saitama 350-0283, Japan
Saini Kethireddy
College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
Katherine M. Bonefas
Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA
Alex Chen
Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA
Brendan L.M. Sutton
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
Kenjiro Bandow
Meikai University School of Dentistry, Department of Oral Biology and Tissue Engineering, Division of Biochemistry, Sakado, Saitama 350-0283, Japan
Yali Dou
Department of Medicine and Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Shigeki Iwase
Michigan Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Corresponding author
Michael A. Sutton
Michigan Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Corresponding author
Summary: Heterozygous mutations in any of the six H3K4 methyltransferases (KMT2s) result in monogenic neurodevelopmental disorders, indicating non-redundant yet poorly understood roles of this enzyme family in neurodevelopment. However, the specific cellular role of KMT2 enzymes in the brain remains poorly understood, owing to the clear non-catalytic functions of each family member and the potential for functional redundancy in installing H3K4 methylation (H3K4me). Here, we identify an instructive role for H3K4me in controlling synapse function and a division of labor among the six KMT2 enzymes in regulating homeostatic synaptic scaling. Using RNAi screening, conditional genetics, small-molecule inhibitors, and transcriptional profiling, our data reveal that individual KMT2 enzymes have unique roles and operate in specific phases to control distinct facets of homeostatic scaling. Together, our results suggest that the expansion of this enzyme family in mammals is key to coupling fine-tuned gene expression changes to adaptive modifications of synaptic function.
