Neuronal CTCF Is Necessary for Basal and Experience-Dependent Gene Regulation, Memory Formation, and Genomic Structure of BDNF and Arc

Dev Sharan Sams,Stefano Nardone,Dmitriy Getselter,Dana Raz,Moran Tal,Prudhvi Raj Rayi,Hanoch Kaphzan,Ofir Hakim,Evan Elliott

doi:10.1016/j.celrep.2016.11.004

Dev Sharan Sams, Stefano Nardone + Show 7 more

Open Access

https://doi.org/10.1016/j.celrep.2016.11.004

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Journal: Cell Reports	Publication Date: Nov 1, 2016
Citations: 84	License type: cc-by

Affiliation: Bar-Ilan University, University of Haifa

Abstract

CCCTC-binding factor (CTCF) is an organizer of higher-order chromatin structure and regulates gene expression. Genetic studies have implicated mutations in CTCF in intellectual disabilities. However, the role of CTCF-mediated chromatin structure in learning and memory is unclear. We show that depletion of CTCF in postmitotic neurons, or depletion in the hippocampus of adult mice through viral-mediated knockout, induces deficits in learning and memory. These deficits in learning and memory at the beginning of adulthood are correlated with impaired long-term potentiation and reduced spine density, with no changes in basal synaptic transmission and dendritic morphogenesis and arborization. Cognitive disabilities are associated with downregulation of cadherin and learning-related genes. In addition, CTCF knockdown attenuates fear-conditioning-induced hippocampal gene expression of key learning genes and loss of long-range interactions at the BDNF and Arc loci. This study thus suggests that CTCF-dependent gene expression regulation and genomic organization are regulators of learning and memory.

Highlights

Epigenetic regulation of neuronal gene expression in the hippocampus plays a primary role in learning and memory (Miller et al, 2008)
Using conditional knockout mice and adenoviral-mediated knockout of CTCF in the hippocampus, coupled with genome-wide gene expression and circular chromosome conformation capture (4C), we find a vital role for CTCF-mediated gene expression in the formation of hippocampal-dependent memory
Characterization of CTCF in the Mouse Brain Initially, we characterized the temporal and spatial expression of CTCF in the mouse brain. Both CTCF mRNA transcripts and protein were detected in whole-brain extracts throughout development

Summary

Introduction

Epigenetic regulation of neuronal gene expression in the hippocampus plays a primary role in learning and memory (Miller et al, 2008). Histone deacetylases (e.g., HDAC2 and HDAC4) regulate learning and memory by modifying histone acetylation levels at learning-associated genes (Guan et al, 2009; Kim et al, 2012). Besides histone acetylation, another epigenetic marker, DNA methylation, has been demonstrated to regulate memory. While the emerging field of behavioral epigenetics has determined the importance of local epigenetic modifications in the regulation of learning-related genes, the roles of three-dimensional DNA structure and high-order genomic organization are largely unknown

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