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Remote Memory and Cortical Synaptic Plasticity Require Neuronal CCCTC- Binding Factor (CTCF)

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Remote Memory and Cortical Synaptic Plasticity Require Neuronal CCCTC- Binding Factor (CTCF) This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Cellular/Molecular Remote memory and cortical synaptic plasticity require neuronal CCCTC- binding factor (CTCF) Somi Kim1, Nam-Kyung Yu1, Kyu-Won Shim2, Ji-il Kim1, Hyopil Kim1, Dae Hee Han1, Ja Eun Choi1, Seung-Woo Lee1, Dong Il Choi1, Myung Won Kim1, Dong-Sung Lee3, Kyungmin Lee4, Niels Galjart5, Yong-Seok Lee6, Jae-Hyung Lee7 and Bong-Kiun Kaang1 1Department of Biological Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Gwanak-gu, Seoul 08826, South Korea 2Interdisciplinary Program in Bioinformatics, Seoul National University, 1 Gwanangno, Gwanak-gu, Seoul 08826, South Korea 3Salk Institute for Biological Studies, 10010 N Torrey Pines Rd. La Jolla, CA 92130, USA 4Department of Anatomy, Graduate School of Medicine, Kyungpook National University, 2-101, Dongin-dong, Jung-gu, Daegu 700-422, Korea 5Department of Cell Biology and Genetics, Erasmus MC, 3000 CA Rotterdam, The Netherlands 6Department of Physiology, Seoul National University College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul 03080, South Korea 7Department of Life and Nanopharmaceutical Sciences, Department of Maxillofacial Biomedical Engineering, School of Dentistry, Kyung Hee University, Seoul 02447, South Korea DOI: 10.1523/JNEUROSCI.2738-17.2018 Received: 21 September 2017 Revised: 30 March 2018 Accepted: 8 April 2018 Published: 30 April 2018 Author contributions: B.-K.K., N.-K.Y., K.-M.L., Y.-S.L., J.-H.L., and S.K. designed research; N.-K.Y., K.-W.S., D.-H.H., H.K., J.E.C., J.-i.K., S.-W.L., D.I.C., M.W.K., J.-H.L., and S.K. performed research; N.G. contributed unpublished reagents/analytic tools; N.-K.Y., K.-W.S., D.-H.H., H.K., J.E.C., J.-i.K., S.-W.L., D.I.C., M.W.K., J.- H.L., S.K., and D.-S.L. analyzed data; B.-K.K., N.-K.Y., K.-M.L., Y.-S.L., J.-H.L., and S.K. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. This work was supported by the National Research Foundation (NRF) of Korea, through grants funded by the Korean government (MSIP) [NRF-2012R1A3A1050385] to B.K.K. J.I.K. was supported by the POSCO TJ Park Foundation. N.-K.Y. was supported by L'Oreal Korea-UNESCO Women in Science fellowship and L'Oreal- UNESCO Rising Talent Award. The authors declare no competing financial interests. Correspondence should be addressed to Bong-Kiun Kaang, Department of Biological Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Gwanak-gu, Seoul 08826, South Korea, [email protected] Cite as: J. Neurosci ; 10.1523/JNEUROSCI.2738-17.2018 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2018 the authors 1 Remote memory and cortical synaptic plasticity require neuronal CCCTC-binding 2 factor (CTCF) 3 4 Somi Kim1,*, Nam-Kyung Yu1,*, Kyu-Won Shim2, Ji-il Kim1, Hyopil Kim1, Dae Hee Han1, Ja 5 Eun Choi1, Seung-Woo Lee1, Dong Il Choi1, Myung Won Kim1, Dong-Sung Lee3, Kyungmin 6 Lee4, Niels Galjart5, Yong-Seok Lee6, Jae-Hyung Lee7, and Bong-Kiun Kaang1,# 7 8 1Department of Biological Sciences, College of Natural Sciences, Seoul National University, 9 1 Gwanangno, Gwanak-gu, Seoul 08826, South Korea 10 2Interdisciplinary Program in Bioinformatics, Seoul National University, 1 Gwanangno, 11 Gwanak-gu, Seoul 08826, South Korea 12 3Salk Institute for Biological Studies, 10010 N Torrey Pines Rd. La Jolla, CA 92130, USA 13 4Department of Anatomy, Graduate School of Medicine, Kyungpook National University, 2- 14 101, Dongin-dong, Jung-gu, Daegu 700-422, Korea 15 5Department of Cell Biology and Genetics, Erasmus MC, 3000 CA Rotterdam, The 16 Netherlands 17 6Department of Physiology, Seoul National University College of Medicine, 103 Daehak-ro, 18 Jongro-gu, Seoul 03080, South Korea 19 7Department of Life and Nanopharmaceutical Sciences, Department of Maxillofacial 20 Biomedical Engineering, School of Dentistry, Kyung Hee University, Seoul 02447, South 21 Korea 1 22 23 *These authors contributed equally to this work. 24 25 #Correspondence should be addressed to Bong-Kiun Kaang, Department of Biological 26 Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Gwanak-gu, 27 Seoul 08826, South Korea, [email protected]. 28 29 Running title: CTCF regulation of remote memory 30 Number of pages: 28 31 Number of figures: 6 32 Number of tables: 2 33 Number of words for Abstract: 222 34 Number of words for Introduction: 649 35 Number of words for Discussion: 1173 36 37 ACKNOWLEDGEMENTS 38 This work was supported by the National Research Foundation (NRF) of Korea, through 39 grants funded by the Korean government (MSIP) [NRF-2012R1A3A1050385] to B.K.K. 40 J.I.K. was supported by the POSCO TJ Park Foundation. N.-K.Y. was supported by L’Oreal 41 Korea-UNESCO Women in Science fellowship and L’Oreal-UNESCO Rising Talent Award. 42 The authors declare no competing financial interests. 2 43 44 ABSTRACT 45 The molecular mechanism of long-term memory has been extensively studied in the context 46 of the hippocampus-dependent recent memory examined within several days. However, 47 months-old remote memory maintained in the cortex for long-term has not been investigated 48 much at the molecular level yet. Various epigenetic mechanisms are known to be important 49 for long-term memory, but how the three-dimensional (3D) chromatin architecture and its 50 regulator molecules contribute to neuronal plasticity and systems consolidation are still 51 largely unknown. CCCTC-binding factor (CTCF) is an eleven-zinc finger protein well known 52 for its role as a genome architecture molecule. Male conditional knockout (cKO) mice in 53 which CTCF is lost in excitatory neurons during adulthood showed normal recent memory in 54 the contextual fear conditioning and spatial water maze tasks. However, they showed 55 remarkable impairments in remote memory in both tasks. Underlying the remote memory- 56 specific phenotypes, we observed that female CTCF cKO mice exhibit disrupted cortical 57 long-term potentiation (LTP), but not hippocampal LTP. Similarly, we observed that CTCF 58 deletion in inhibitory neurons caused partial impairment of remote memory. Through RNA- 59 sequencing, we observed that CTCF knockdown in cortical neuron culture caused altered 60 expression of genes that are highly involved in cell adhesion, synaptic plasticity, and memory. 61 These results suggest that remote memory storage in the cortex requires CTCF-mediated 62 gene regulation in neurons while recent memory formation in the hippocampus does not. 63 64 SIGNIFICANCE STATEMENT 3 65 CTCF is a well-known 3D genome architectural protein that regulates gene expression. Here, 66 we use two different CTCF conditional knockout mouse lines and reveal for the first time that 67 CTCF is critically involved in the regulation of remote memory. We also show that CTCF is 68 necessary for appropriate expression of genes, many of which we found to be involved in the 69 learning and memory related processes. Our study provides behavioral and physiological 70 evidence for the involvement of CTCF-mediated gene regulation in the remote long-term 71 memory and elucidates our understanding of systems consolidation mechanisms. 72 73 INTRODUCTION 74 The formation of long-term memory in the brain involves dynamic gene regulation through 75 multiple layers of mechanisms. This has been established based on studies focusing on the 76 recent long-term memory, which is typically examined one to several days after learning (Lee 77 et al., 2007; Huang et al., 2013; Nagayoshi et al., 2017). However, memory is believed to be 78 further processed into remote long-term memory over several weeks after the initial 79 consolidation, during which the major brain region preserving the memory is shifted from the 80 hippocampus to the cortex; this process is called systems consolidation (Frankland et al., 81 2004; Wang et al., 2006). During systems consolidation, cortical neural circuits bearing 82 memory traces are reorganized and strengthened, leading to stabilization of the memory for 83 long-term storage. 84 For the expression of remote memory, anterior cingulate cortex (ACC) has been noted to be 85 particularly important among several brain regions (Einarsson et al., 2014). Several studies 86 have shown that ACC is critical for remote fear and spatial memories (Frankland et al., 2004) 87 (Teixeira et al., 2006). More recent studies have shown that optogenetic inhibition of ACC 88 (Goshen et al., 2011) and a disruption of spine growth in ACC (Restivo et al., 2009) block the 4 89 contextual fear memory, suggesting that structural modifications in ACC is important for 90 remodeling of long-range cortical connections during systems consolidation. Some previous 91 studies have shown that epigenetic mechanisms are involved in systems consolidation. For 92 example, cortical DNA methylation and histone acetylation participate in the formation 93 and/or maintenance of remote memory (Miller et al., 2010; Yu et al., 2011; Peixoto and Abel, 94 2013). However, much of systems consolidation process still remains elusive and the exact 95 molecular underpinning of how remote memory is regulated is yet to be discovered. 96 Recently, three-dimensional (3D) genome architecture has been receiving increasing 97 attention in the research on epigenetic mechanisms (Bonev and Cavalli, 2016). 3D genome 98 organization allows chromatin interaction within the topologically associating domains 99 (TADs), which are genomic regions that frequently make contacts within themselves (Pombo 100 and Dillon, 2015). This provides important structural bases for gene regulation, thereby 101 contributing to the cell-type specific gene expression (Bouwman and de Laat, 2015).
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