A novel environment-evoked transcriptional signature predicts reactivity in single dentate granule neurons

Jaeger, Baptiste N.; Linker, Sara B.; Parylak, Sarah; Barron, Jerika J.; Gallina, Iryna; Saavedra, Christian D; Fitzpatrick, Conor; Lim, Christina; Schäfer, Simon; Lacar, Benjamin; Jessberger, Sebastian; Gage, Fred H.

doi:10.1038/s41467-018-05418-8

Cited by 75 publications

(101 citation statements)

References 82 publications

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“…Single cell RNA-seq on hippocampal dentate granule cells from mice subjected to novel environments shows differences in transcriptomes between sparsley firing neurons in the dentate gyrus versus quiet cells [19]. When profiles are sorted based on FOS expression, MAGIC was able to call FOS as the second most likely driver of gene changes, placing the highly homologous protein FOSL2 as top rank [41].…”

Section: Discussionmentioning

confidence: 99%

“…Single cell transcriptome profiling allows the discerning of responses of individual cells to stimuli. Jaeger et al performed single cell profiling on mouse dentate granule cells in response to a novel location stimulus [19]. Cells were sorted on Fos expression, an Immediate Early Gene (IEG) that is expressed in response to neuronal firing [25].…”

Section: ) Tcga(lum_vs_basal) 233 Luminal-a and 79mentioning

confidence: 99%

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MAGIC: A tool for predicting transcription factors and cofactors driving gene sets using ENCODE data

2020

PLoS Comput Biol

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Transcriptomic profiling is an immensely powerful hypothesis generating tool. However, accurately predicting the transcription factors (TFs) and cofactors that drive transcriptomic differences between samples is challenging. A number of algorithms draw on ChIP-seq tracks to define TFs and cofactors behind gene changes. These approaches assign TFs and cofactors to genes via a binary designation of 'target', or 'non-target' followed by Fisher Exact Tests to assess enrichment of TFs and cofactors. ENCODE archives 2314 ChIP-seq tracks of 684 TFs and cofactors assayed across a 117 human cell lines under a multitude of growth and maintenance conditions. The algorithm presented herein, Mining Algorithm for GenetIc Controllers (MAGIC), uses ENCODE ChIP-seq data to look for statistical enrichment of TFs and cofactors in gene bodies and flanking regions in gene lists without an a priori binary classification of genes as targets or non-targets. When compared to other TF mining resources, MAGIC displayed favourable performance in predicting TFs and cofactors that drive gene changes in 4 settings: 1) A cell line expressing or lacking single TF, 2) Breast tumors divided along PAM50 designations 3) Whole brain samples from WT mice or mice lacking a single TF in a particular neuronal subtype 4) Single cell RNAseq analysis of neurons divided by Immediate Early Gene expression levels. In summary, MAGIC is a standalone application that produces meaningful predictions of TFs and cofactors in transcriptomic experiments.

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Section: Discussionmentioning

confidence: 99%

Section: ) Tcga(lum_vs_basal) 233 Luminal-a and 79mentioning

confidence: 99%

MAGIC: A tool for predicting transcription factors and cofactors driving gene sets using ENCODE data

2020

PLoS Comput Biol

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“…Which aspects of ENR and the mechanisms how environmental stimulation prevents age-related DNA methylation changes remains to be investigated. Previous work has shown that exploration of novel environments leads to neuronal activation coupled with short-term and long-lasting changes in transcription and chromatin accessibility in activated hippocampal neurons 55, 56 . Additionally, isolated neuronal activation by electroconvulsive stimulation has been shown to lead to widespread changes in DNA methylation, RNA and open chromatin landscapes in the dentate gyrus 16, 35 .…”

Section: Discussionmentioning

confidence: 99%

Epigenetic rejuvenation of the hippocampus by environmental enrichment

Zocher

Overall

Lesche

et al. 2019

Preprint

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10The decline of brain function during aging is associated with epigenetic changes, including DNA 11 methylation. Lifestyle interventions can improve brain function during aging, but their influence 12 on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, 13 we here show that environmental enrichment counteracted age-related DNA methylation changes 14 in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the 15 aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, 16 which is known to control neuronal functions. The genes at which environmental enrichment 17 counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication 18 and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the 19 human brain. Our results highlight the rejuvenating effects of environmental enrichment at the level 20 of DNA methylation and give molecular insights into the specific aspects of brain aging that can 21 be counteracted by lifestyle interventions. 22

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“…To test this notion, DGCs, activated by a 15 min exposure to a novel environment, were isolated 60 min later for single-nucleus genome-wide bisulfite sequencing (snRRBS). PROX + DGC nuclei, expressing the IEG protein FOS, a proxy for neuronal activity, were sorted from PROX + /FOScells from dissected dorsal hippocampi by FACS 28,42 (Fig. 5a).…”

Section: Mainmentioning

confidence: 99%

Epigenetically bistable regions across neuron-specific genes govern neuron eligibility to a coding ensemble in the hippocampus

Shannon

Taki

Klein

et al. 2019

Preprint

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Episodic memories are stored in distributed neurons but how eligibility of individual neurons to coding ensembles is determined remains elusive. We identified thousands of predominantly bistable (CpG methylated or unmethylated) regions within neuronal gene bodies, established during the development of the mouse hippocampal dentate gyrus. Reducing DNA methylation and the proportion of the methylated epialleles at bistable regions compromised novel context-induced neuronal activation and spatial memory. Conversely, increasing methylation and the frequency of the methylated epialleles at bistable regions enhanced intrinsic excitability and spatial memory but impaired spatial working memory, indicating that the developmentally established methylated-unmethylated epiallelic balance at bistable regions is essential for proper neuronal excitability and hippocampal cognitive functions. Single-nucleus profiling revealed the enrichment of specific epialleles from a subset of bistable regions, primarily exonic, in encoding neurons. We propose a model in which epigenetically bistable regions create neuron heterogeneity, and specific constellations of exonic epialleles dictate, via modulating neuronal excitability, eligibility to a coding ensemble.Bidirectional manipulation of the relative frequency of the methylated epialleles in vivo reduced and increased neuronal intrinsic excitability, novel context-induced neuronal activation, and hippocampal functions, linking methylation states and the combinations of these states, to neuronal eligibility to coding. Single-nucleus profiling of recently recruited neurons revealed enrichment for a set of epialleles that, via gene expression, may underlie eligibility for coding environmental inputs. Through these findings, our work implicates an epigenetic mechanisms dictating neuronal eligibility to recruitment, the first step of memory formation. Results:We found evidence for the developmental emergence of epigenetic heterogeneity in otherwise morphologically homogenous and genetically identical dorsal (d) DGCs in C57BL/6 male mice 15 .DGCs or their progenitors were microdissected from the granule cell layer of d (d) hippocampal slices at either embryonic day (E) 10.5, postnatal day (P) 6 or at 10-12 weeks of age, followed by enhanced RRBS methylation profiling of 1.5-2.5 million cytosines 16 (Fig. 1a). Loss and gain of methylation during the transition of P6 young DGCs (yDGCs) to adult DGCs produced 170,198 differentially methylated (DM) CpG sites (q<0.01, RRBS at >10x coverage, average change 22.23%). In adult DGCs, these DM CpGs were by and large not fully methylated and unmethylated but rather were in the state of intermediate methylation (IM, i.e. were methylated across the entire 0% to 100% range, Fig. 1c, pink). Many of these sites were already IM at P6 ( Fig. 1c, blue) indicating that the partial methylation/demethylation process began earlier.Indeed, comparing adult DGCs with cells from an earlier developmental stage, E10.5 hippocampal progenitors (HPs), still yielded DM sites ...

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A novel environment-evoked transcriptional signature predicts reactivity in single dentate granule neurons

Cited by 75 publications

References 82 publications

MAGIC: A tool for predicting transcription factors and cofactors driving gene sets using ENCODE data

MAGIC: A tool for predicting transcription factors and cofactors driving gene sets using ENCODE data

Epigenetic rejuvenation of the hippocampus by environmental enrichment

Epigenetically bistable regions across neuron-specific genes govern neuron eligibility to a coding ensemble in the hippocampus

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