DNA methylation changes in plasticity genes accompany the formation and maintenance of memory

Abstract

Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms † Correspondence to ; Email: mikeh@alleninstitute.org, ; Email: edl@alleninstitute.org 2 These authors contributed equally to this study. AUTHOR CONTRIBUTIONS HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptThe structure and function of the human brain are highly stereotyped, implying a conserved molecular program responsible for its development, cellular structure, and function. We applied a correlation-based metric of "differential stability" (DS) to assess reproducibility of gene expression patterning across 132 structures in six individual brains, revealing meso-scale genetic organization. The highest DS genes are highly biologically relevant, with enrichment for brainrelated biological annotations, disease associations, drug targets, and literature citations. Using high DS genes we identified 32 anatomically diverse and reproducible gene expression signatures, which represent distinct cell types, intracellular components, and/or associations with neurodevelopmental and neurodegenerative disorders. Genes in neuron-associated compared to non-neuronal networks showed higher preservation between human and mouse; however, many diversely-patterned genes displayed dramatic shifts in regulation between species. Finally, highly consistent transcriptional architecture in neocortex is correlated with resting state functional connectivity, suggesting a link between conserved gene expression and functionally relevant circuitry.The adult human brain is composed of many regions with distinct distributions of cell types and patterns of functional connectivity. Underlying this complexity is differential transcription, whereby different brain regions and their constituent cell types express unique combinations of genes during their developmental specification and maturation and in their mature functional state. Despite a range of brain sizes across individuals and variation in sulcal patterning in the neocortex, the general anatomical positioning of and connectivity between regions is highly stereotyped between individuals, suggesting that a significant proportion of the transcriptional coding for this common architecture is conserved across the human population.We aimed to identify the core or "canonical" transcriptional machinery conserved across individuals, in contrast to numerous studies that explore genetic variants associated with disease traits by analyzing enormous sample sizes in population studies 1 , 2 . If common expression relationships can be identified with high confidence in modest sample sizes and with good anatomical coverage of various brain regions, the resulting "default gene network" could provide a base template for understanding the genetic underpinnings of highly conserved features of brain organization and a b...

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“…MeDIP. Sample preparation for MeDIP and sequencing was conducted as described previously (58). We isolated the mPFC from five mice at 3 mo of age and performed MeDIP sequencing for all five samples.…”

“…The program ngsplot was used to plot the DNAme across the high-, medium-, and low-expressed genes. Genes ware classified into high-, medium-, and low-expressed according to expression level as mentioned earlier (58). Briefly, we calculated the fragments per kilobase of exon per million reads (FPKM) values for the genes of the RNA-sequencing data from the same region from wild-type mice (n = 3) using cufflinks.…”

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“…These results suggest that a substantial proportion of differentially methylated regions might regulate transcription factor binding in cis -regulatory regions. Fischer and Bonn groups also demonstrated directly lasting memory-associated changes in DNA methylation in the cortex (Haider et al, 2016). Their comprehensive genome-wide assessments strongly support the hypothesis that DNA cytosine methylation contributes to long-term memory stabilization and storage in vivo.…”

“…More recent work identified DNA methylation changes that are associated with contextual fear memory consolidation and maintenance (Haider et al, 2016). They charted an unbiased genome-wide profile of DNA methylation, brain region (hippocampal CA1 and anterior cingulate cortex) and cell type specificity (neuron and non-neuron), over time (1 h and 4 weeks after learning), and found that substantial changes in DNA methylation during memory consolidation and maintenance are present at specific inter- and intragenic regions.…”

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“…Epigenetic mechanisms are particularly intriguing candidates to explore in SEFL because even transient modifications can produce persistent gene and protein expression changes (Weaver et al 2004;Kumar et al 2005). Further, DNA methylation and some chromatin modifications associated with both stress and fear memory can, themselves, persist for very long periods of time (Miller et al 2010;Stankiewicz et al 2013;Halder et al 2016). The brain may be made more vulnerable to "overconsolidation" of a pathological memory by a stressful experience through transient or persistent, gene-specific epigenetic changes triggered by the stressor in brain regions affected by both stress and fearful associations, such as the amygdala (e.g., epigenetic repression of memory suppressors, such as PP1 and calcineurin; Miller and Sweatt 2007;Baumgartel et al 2008;Herzog et al 2008;Miller et al 2010).…”