Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression

Beagan, Jonathan A.; Pastuzyn, Elissa D.; Fernandez, Lindsey R.; Guo, Michael H.; Feng, Kelly; Titus, Katelyn R.; Chandrashekar, Harshini; Shepherd, Jason D.; Phillips-Cremins, Jennifer E.

doi:10.1038/s41593-020-0634-6

Cited by 113 publications

(126 citation statements)

References 68 publications

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“…However, given that mRNA splicing is co-transcriptional in neurons ( 66 ), we predict that this would only have minor effects. While we included earlier time points than previous studies to capture the window in which eRNA and mRNA are first induced, our data corroborate the described dynamics of eRNA transcription as well as recently identified activity-induced rapid enhancer–promoter interactions ( 15 , 33 , 39 ). Our results extend these findings and show that eRNA transcription in response to activity is rapid and follows distinct temporal profiles as compared to mRNA from linked genes (Figure 3J ).…”

Section: Resultssupporting

confidence: 83%

“…A recent study by Beagan et al. assessed activity-dependent chromatin restructuring and enhancer–promoter loops and found activity-responsive looping between the Fos promoter and enhancer-1 but not enhancer-3 ( 39 ). Existing enhancer-promoter interaction could potentially be required for acRNA mediated effects.…”

Section: Resultsmentioning

confidence: 99%

“…Recent work by Beagan et al. examined three-dimensional chromatin structure changes in response to neuronal activity, and demonstrated the formation of enhancer-promoter loops within 20 min of stimulation at IEGs including the Fos gene ( 39 ). Consistent with our findings, this report also showed increased eRNA and enhancer–promoter interaction changes prior to induction of mRNA from these loci.…”

Section: Discussionmentioning

confidence: 99%

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Enhancer RNAs predict enhancer–gene regulatory links and are critical for enhancer function in neuronal systems

Carullo

Phillips

Simon

et al. 2020

Nucleic Acids Research

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Genomic enhancer elements regulate gene expression programs important for neuronal fate and function and are implicated in brain disease states. Enhancers undergo bidirectional transcription to generate non-coding enhancer RNAs (eRNAs). However, eRNA function remains controversial. Here, we combined Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq) and RNA-Seq datasets from three distinct neuronal culture systems in two activity states, enabling genome-wide enhancer identification and prediction of putative enhancer–gene pairs based on correlation of transcriptional output. Notably, stimulus-dependent enhancer transcription preceded mRNA induction, and CRISPR-based activation of eRNA synthesis increased mRNA at paired genes, functionally validating enhancer–gene predictions. Focusing on enhancers surrounding the Fos gene, we report that targeted eRNA manipulation bidirectionally modulates Fos mRNA, and that Fos eRNAs directly interact with the histone acetyltransferase domain of the enhancer-linked transcriptional co-activator CREB-binding protein (CBP). Together, these results highlight the unique role of eRNAs in neuronal gene regulation and demonstrate that eRNAs can be used to identify putative target genes.

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Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Enhancer RNAs predict enhancer–gene regulatory links and are critical for enhancer function in neuronal systems

Carullo

Phillips

Simon

et al. 2020

Nucleic Acids Research

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“…Recently, it has been shown that other distal enhancer regions form chromatin loops with the Bdnf first cluster of exons and the +3 kb enhancer region ( Beagan et al, 2020 ). Similarly, long-distance interactions with the +3 kb enhancer region have been reported in neurons isolated from the human brain ( Nott et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Intronic enhancer region governs transcript-specific Bdnf expression in rodent neurons

Tuvikene

Esvald

Rähni

et al. 2021

eLife

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Brain-derived neurotrophic factor (BDNF) controls the survival, growth, and function of neurons both during the development and in the adult nervous system. Bdnf is transcribed from several distinct promoters generating transcripts with alternative 5' exons. Bdnf transcripts initiated at the first cluster of exons have been associated with the regulation of body weight and various aspects of social behavior, but the mechanisms driving the expression of these transcripts have remained poorly understood. Here, we identify an evolutionarily conserved intronic enhancer region inside the Bdnf gene that regulates both basal and stimulus-dependent expression of the Bdnf transcripts starting from the first cluster of 5' exons in mouse and rat neurons. We further uncover a functional E-box element in the enhancer region, linking the expression of Bdnf and various pro-neural basic helix-loop-helix transcription factors. Collectively, our results shed new light on the cell-type- and stimulus-specific regulation of the important neurotrophic factor BDNF.

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“…Notably, we observed YY1 signal at an H3K27ac-enriched enhancer region ~15 kb upstream of the Fos TSS (Fig 5m). H3K27ac signal at this enhancer was recently linked to the activation of Fos expression in murine primary cultured neurons 64 , suggesting that YY1 binding at this enhancer may regulate Fos transcription.…”

Section: Given That Our Experimental and Computational Analyses Uncovmentioning

confidence: 98%

Stress-induced epigenetic regulation of transcription in neocortical excitatory neurons drives depression-like behavior

Kwon

Zhao

et al. 2020

Preprint

Self Cite

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ABSTRACTProlonged stress exposure is a major risk factor for the development of depression and comorbid anxiety. Efforts to understand how recurrent stress induces behavioral maladaptation have largely concentrated on the neuronal synapse with limited understanding of the underlying epigenetic mechanisms. Here, we performed complementary bulk nuclei- and single-nucleus transcriptome profiling and mapped fine-scale chromatin architecture in mice subjected to chronic unpredictable stress (CUS) to identify the cell type-specific epigenetic alterations that drive complex behavior. We find that neocortical excitatory neurons are particularly vulnerable to chronic stress and acquire signatures of transcription and chromatin configuration that denote reduced neuronal activity and expression of Yin Yang 1 (YY1). Selective ablation of YY1 in excitatory neurons of the prefrontal cortex (PFC) enhances stress sensitivity in mice, inducing depressive- and anxiety-related behaviors and deregulating the expression of stress-associated genes following an abbreviated stress exposure. Notably, we find that loss of YY1 in PFC excitatory neurons provokes more maladaptive behaviors in stressed females than males. These findings demonstrate how chronic stress provokes maladaptive behavior by epigenetically shaping excitatory neurons in the PFC, identifying a novel molecular target for therapeutic treatment of stress-related mood and anxiety disorders.

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Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression

Cited by 113 publications

References 68 publications

Enhancer RNAs predict enhancer–gene regulatory links and are critical for enhancer function in neuronal systems

Enhancer RNAs predict enhancer–gene regulatory links and are critical for enhancer function in neuronal systems

Intronic enhancer region governs transcript-specific Bdnf expression in rodent neurons

Stress-induced epigenetic regulation of transcription in neocortical excitatory neurons drives depression-like behavior

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