Activity-dependent remodeling of genome architecture in engram cells facilitates memory formation and recall

Abstract

The formation and preservation of long-term memories critically depend upon coordinated activity of neuronal circuits, intracellular signaling cascades and synaptic remodeling (Josselyn et al., 2015). These essential processes occur in specific cell populations known as the engram ensemble (Josselyn et al., 2015). The current model for engram formation suggests that an experience activates a sub-population of neurons that can be measured by the expression of immediate early genes (IEG), such as Arc (activity regulated cytoskeleton associated protein, Arg3.1) or cFos (Fos Proto-Oncogene, AP-1 transcription factor subunit). Activated engram cells are then physically or chemically modified during memory consolidation, where labile memory is transformed into a more stable and long-lasting state. Notably, the memory consolidation process occurs predominantly long after the initial stimulus had ceased and the engram cells are in a dormant or a quiescent state. Reactivation of the engram ensemble by subsequent presentation of the original stimuli results in memory retrieval. Therefore, temporal progressions of memory formation from learning to retrieval require several waves of delayed transcriptional and translational alterations (Josselyn et al., 2015). Nonetheless, the molecular mechanisms that enable this temporal and spatial synchronization remain elusive. Epigenetic modulation and three-dimensional (3D)-genome architecture are emerging as key factors in mediating activity-dependent genes programs in numerus brain functions, including neurodevelopment, neurogenesis and neuronal properties (Malik et al., 2014; Rajarajan et al., 2016; Fernandez-Albert et al., 2019; Yamada et al., 2019). Here, we review recent studies that indicate an important role for chromatin accessibility and spatial nuclear architecture in facilitating critical aspects of learning and memory. This additional layer of evidence not only has significant implications for understanding neuronal plasticity, learning and memory, but also could enable the identification of novel disease risk factors in many cognitive and memory related disorders. The term ‘epigenetics’ refers to external chemical modifications to the DNA or proteins associated with DNA that affect how cells will “read” and use the genes, without changing the DNA sequence itself (Rajarajan et al., 2016). In the cell nucleus, DNA exists in a complex with histone proteins, called chromatin. Epigenetic modifications alter chromatin structure and DNA accessibility. Generally, when chromatin is tightly packed or the DNA is blocked by methyl molecules (i.e., DNA methylation), nearby genes will not be expressed. However, open or relaxed chromatin state creates a permissible environment that enables the binding of the transcriptional machinery, and thereby controls and enhances gene expression (Rajarajan et al., 2016). Although high-resolution mapping of the epigenome, including whole genome DNA methylation and chromatin immunoprecipitation sequencing has enabled the linear genome to be understood, these data does not account for the spatial configuration of chromatin. Thus, a comprehensive exploration of the genome has to go far beyond measuring linear epigenetic properties. New approaches such as chromosome conformation capture (3C) techniques allow us to map 3D-chromatin contacts on a genome-wide scale and demonstrate multiple levels of nuclear organization (Rajarajan et al., 2016). These include the configuration of chromosome in territories and their interaction with one another and with the nuclear lamina, which has a profound effect on gene expression (Rajarajan et al., 2016). Furthermore, chromatin is segregated into two sub-nuclear compartments; ‘A compartment’, which is enriched for accessible chromatin and correspond to higher overall levels of transcription, and ‘B compartment’ that harbor the transcriptionally inactive and less accessible (heterochromatin) regions of the genome. Interestingly, early evidences suggest that neuronal activity induces re-organization in compartments and large scale 3D-chromatin structures (Rajarajan et al., 2016; Fernandez-Albert et al., 2019; Yamada et al., 2019), indicating that chromatin organization might be highly responsive to external stimuli. The genome is further organized into self-interacting units called topologically associated domains (TADs) which are demarcated by clear boundaries. Furthermore, new observation from detailed 3D-contacts genomic maps indicated that smaller chromatin domains, so-called subTADs, are nested hierarchically within TADs. Nested subTADs are also demarcated by boundaries, however exhibit weaker insulation strength and might have different functional properties. How TADs, subTADs and compartment domains are uniquely defined by their structural and mechanistic properties remains an open question. Several lines of evidence support a model of bidirectional structure–function relationship which is determined by tr