Chromatin-mediated alternative splicing regulates cocaine-reward behavior

Xu, Song Jun; Lombroso, Sonia I.; Fischer, Delaney K.; Carpenter, Marco D.; Marchione, Dylan M.; Hamilton, Peter J.; Lim, Carissa J.; Neve, Rachel L.; Garcia, Benjamin A.; Wimmer, Mathieu E.; Pierce, R. Christopher; Heller, Elizabeth A.

doi:10.1016/j.neuron.2021.08.008

Cited by 49 publications

(32 citation statements)

References 151 publications

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“…We found that ICuRuS generated robust and reproducible H3K4me3 and H3K27me3 profiles at sufficient depth to examine cell-type specific chromatin from a single mouse striatum. These findings are an improvement over current methods, such as bulk tissue CnR 25 , which obscures cell-type specificity, and single-cell CnR, which requires pooled brain tissue and obscures subject variability 1 . Analysis of a single brain region from a single mouse overcomes a critical barrier given individual differences in stimulus-induced gene expression and susceptibility to psychiatric disease 40 , 41 .…”

Section: Discussionmentioning

confidence: 94%

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Cell-type specific profiling of histone post-translational modifications in the adult mouse striatum

et al. 2022

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Epigenetic gene regulation in the heterogeneous brain remains challenging to decipher with current strategies. Bulk tissue analysis from pooled subjects reflects the average of cell-type specific changes across cell-types and individuals, which obscures causal relationships between epigenetic modifications, regulation of gene expression, and complex pathology. To address these limitations, we optimized a hybrid protocol, ICuRuS, for the isolation of nuclei tagged in specific cell-types and histone post translational modification profiling from the striatum of a single mouse. We combined affinity-based isolation of the medium spiny neuron subtypes, Adenosine 2a Receptor or Dopamine Receptor D1, with cleavage of histone-DNA complexes using an antibody-targeted micrococcal nuclease to release DNA complexes for paired end sequencing. Unlike fluorescence activated cell sorting paired with chromatin immunoprecipitation, ICuRuS allowed for robust epigenetic profiling at cell-type specific resolution. Our analysis provides a framework to understand combinatorial relationships between neuronal-subtype-specific epigenetic modifications and gene expression.

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Section: Discussionmentioning

confidence: 94%

“…Fluorescence microscopy showed a sufficient number of nuclei (8000 -10,000) were recovered for downstream hPTM profiling by CnR (Fig. 1E ) 13 , 23 – 25 and mRNA quantification by qPCR of high quality mRNA (Supplementary Fig. 1B ).…”

Section: Resultsmentioning

confidence: 99%

Cell-type specific profiling of histone post-translational modifications in the adult mouse striatum

et al. 2022

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“…In contrast, upregulation of circAnks1a, circSlc24a2 and circUbe2cbp was not accompanied by a change in linear mRNA levels and may be due to heroin-induced modulation of a splicing factor. Drug-induced regulation of splicing factors has been previously reported [49,50].…”

Section: Discussionmentioning

confidence: 98%

Heroin Regulates Orbitofrontal Circular RNAs

Floris

Gillespie

Zanda

et al. 2022

IJMS

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The number of drug overdose deaths involving opioids continues to rise in the United States. Many patients with opioid use disorder (OUD) that seek treatment still experience relapse. Perseverant opioid seeking behaviors represent a major challenge to treating OUD and additional therapeutic development will require insight into opioid-induced neurobiological adaptations. In this study, we explored the regulation of a novel class of RNAs, circular RNAs (circRNAs), by the addictive opioid heroin in the rat orbitofrontal cortex (OFC), a brain region that mediates behavioral responses to rewarding stimuli. Microarray analysis identified 76 OFC circRNAs significantly regulated in male rats after heroin self-administration. We evaluated the specificity of these findings by measuring heroin-associated circRNA expression in female rats after heroin self-administration and in rats that self-administered sucrose. We identify circGrin2b, circUbe2cp, circAnks1a, circAdcy5 and circSlc24A2 as heroin-responsive circRNAs in the OFC. Linear mRNA levels of heroin-associated circRNAs were unchanged except for Grin2b and Adcy5. An integrated bioinformatics analysis of regulated circRNAs identified microRNAs predicted to bind heroin-associated circRNAs and downstream targets of circRNA: microRNA sponging. Thus, heroin regulates the expression of OFC RNA splice variants that circularize and may impact cellular processes that contribute to the neurobiological adaptations that arise from chronic heroin exposure.

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“…This will require more accurate and complete maps of the genes controlled by a given enhancer region, which must be determined for each cell type of interest. Indeed, our efforts benefit from a large repository of ChIP-seq and CUT&RUN-seq data for numerous histone modifications and chromatin-regulatory proteins in NAc, many in D1 and D2 MSNs selectively, which enable a comprehensive understanding of the regulation of gene expression through enhancer mechanisms in these two cell types [33][34][35][36][37][38] . Since enhancer function is also controlled by the 3D structure of chromatin, as noted above, which can bring a distant enhancer into close proximity to a gene promoter through chromosomal looping, it will be important to generate 3D maps of chromatin interactions, such as by use of HiC 39 , for D1 and D2 MSNs under control and cocaine conditions-maps which are not yet available.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that alternative splicing can be determined not only by the splicing machinery, but also by transcription factors and chromatin structure 35,36 . To examine whether ∆FOSB binding sites within gene bodies are related to alternative splicing, we compared the locations of ∆FOSB peaks to the alternative-splicing junctions identified in NAc under cocaine and saline self-administration conditions in a recent study 37 . Nine hundred and nine junctions represented differential alternative splicing events (p-value < 0.05 and ∆ percentage spliced in > 0.1), but only 19 of them have detectable ∆FOSB binding sites within 1,000 bp upstream or downstream of their splice donor or acceptor sites (Fig.…”

Section: Lack Of Evidence For a Role Of ∆Fosb In Regulating Alternati...mentioning

confidence: 99%

Cell-type-specific whole-genome landscape of ΔFOSB binding in nucleus accumbens after chronic cocaine exposure

Yeh

Estill

Lardner

et al. 2022

Preprint

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The ability of neurons to respond to external stimuli involves adaptations of gene expression. The transcription factor, ΔFOSB, is important for the development of drug addiction, however, its gene targets have not been identified. Here we use CUT&RUN to map the genome-wide enrichment of ΔFOSB binding in the two major neuronal cell types of the nucleus accumbens, a key brain reward region, after cocaine exposure. The binding landscape shows that the majority of ΔFOSB peaks occur outside of promoter regions, including intergenic regions, and are surrounded by epigenetic marks indicative of active enhancers. BRG1, the core subunit of the SWI/SNF chromatin remodeling complex, overlaps with ΔFOSB peaks, consistent with earlier studies of ΔFOSB's interacting proteins. In addition, in silico analyses predict that ΔFOSB cooperatively regulates gene expression with homeobox and T-box transcription factors. These novel findings uncover key elements of ΔFOSB's molecular mechanisms in transcriptional regulation.

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Chromatin-mediated alternative splicing regulates cocaine-reward behavior

Cited by 49 publications

References 151 publications

Cell-type specific profiling of histone post-translational modifications in the adult mouse striatum

Cell-type specific profiling of histone post-translational modifications in the adult mouse striatum

Heroin Regulates Orbitofrontal Circular RNAs

Cell-type-specific whole-genome landscape of ΔFOSB binding in nucleus accumbens after chronic cocaine exposure

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