The objective of Project 2 is to characterize the involvement of MBT (malignant brain tumor domain) proteins in prefrontal cortex (PFC) and nucleus accumbens (NAc) in mediating depression- and antidepressant-like responses in animal models. MBT proteins are the best known "readers"-i.e., effectors-for several key methylation states of histones, including repessive histone methylation at Lys 9 of histone H3 (H3K9me2). However, virtually nothing is known about the function of MBT proteins in brain. We have found that 3 MBT proteins, L3MBTL1, L3MBTL2, and SFMBT1, are highly expressed in PFC and NAc, where they display dramatic regulation in response to several forms of chronic stress. Depressed humans show similar altered levels of some of these same MBT proteins. Moreover, mice lacking L3MBTL1 show a pro-depression-like phenotype, consistent with findings in Project 1 that downregulation of H3K9me2 increases susceptibility to chronic stress. We have generated mutant lines of the other MBT proteins and now propose the comprehensive characterization of: 1) the regulation of L3MBTL1, L3MBTL2, and SFMBT1 in our Center's battery of depression models, and 2) the behavioral phenotypes of conditional and brain region-specific knockout, or overexpression, of these three MBT proteins. We will then use our novel method, which permits the genome-wide analysis of chromatin modifications specifically within adult PFC neurons, to map the binding of MBT proteins and their key target sites of histone methylation, including H3K9me2, in PFC neurons in chronic stress models, with parallel studies performed on PFC neurons from depressed humans (Project 4). We will also study conditional knockouts of several key histone methyltransferases, including G9a (with Project 1), which catalyze the methylated histone sites read by MBT proteins, based on the hypothesis that similar phenotypes will be observed. We are particularly excited about comparing preclinical and clinical chromatin datasets through which we will construct, specifically for PFC neurons of mouse and human, a genome-wide map of "epigenetic risk loci" highly relevant for depression. Together, this work provides a template for the analysis of the role played by other histone reader proteins in depression.

Public Health Relevance

Depression has a lifetime risk of ~15% for the U.S. general population, yet available antidepressant therapies are based on serendipitous discoveries over 6 decades ago, and fully treat <50% of all affected individuals. An improved understanding of the molecular basis of depression will lead to improved treatments and diagnostic tests-a high priority for the National Institutes of Health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH096890-03
Application #
8672685
Study Section
Special Emphasis Panel (ZMH1-ERB-S)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$277,377
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Shen, Erica Y; Ahern, Todd H; Cheung, Iris et al. (2015) Epigenetics and sex differences in the brain: A genome-wide comparison of histone-3 lysine-4 trimethylation (H3K4me3) in male and female mice. Exp Neurol 268:21-9
Snyder, Gretchen L; Vanover, Kimberly E; Zhu, Hongwen et al. (2015) Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission. Psychopharmacology (Berl) 232:605-21
Nestler, Eric J (2015) ?FosB: a transcriptional regulator of stress and antidepressant responses. Eur J Pharmacol 753:66-72
Heller, Elizabeth A; Cates, Hannah M; Peña, Catherine J et al. (2014) Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors. Nat Neurosci 17:1720-7
Maze, Ian; Chaudhury, Dipesh; Dietz, David M et al. (2014) G9a influences neuronal subtype specification in striatum. Nat Neurosci 17:533-9
Maze, Ian; Shen, Li; Zhang, Bin et al. (2014) Analytical tools and current challenges in the modern era of neuroepigenomics. Nat Neurosci 17:1476-90
Bharadwaj, Rahul; Peter, Cyril J; Jiang, Yan et al. (2014) Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition. Neuron 84:997-1008
Sarkar, Ambalika; Chachra, Parul; Kennedy, Pamela et al. (2014) Hippocampal HDAC4 contributes to postnatal fluoxetine-evoked depression-like behavior. Neuropsychopharmacology 39:2221-32
Feyder, Michael; Södersten, Erik; Santini, Emanuela et al. (2014) A Role for Mitogen- and Stress-Activated Kinase 1 in L-DOPA-Induced Dyskinesia and ?FosB Expression. Biol Psychiatry :
Dias, Caroline; Feng, Jian; Sun, Haosheng et al. (2014) ?-catenin mediates stress resilience through Dicer1/microRNA regulation. Nature 516:51-5

Showing the most recent 10 out of 33 publications