CREB Binding at the Zfp189 Promoter Within Medium Spiny Neuron Subtypes Differentially Regulates Behavioral and Physiological Adaptations Over the Course of Cocaine Use

Teague, Collin; Picone, Joseph A.; Wright, William J.; Browne, Caleb J.; Silva, Gabriella M.; Futamura, Rita; Minier-Toribio, Angélica; Estill, Molly E.; Ramakrishnan, Aarthi; Martínez-Rivera, Freddyson J.; Godino, Arthur; Parise, Eric M.; Schmidt, Kyra H.; Pulido, Nathalia V.; Lorsch, Zachary S.; Kim, Jee Hyun; Shen, Li; Neve, Rachael L.; Dong, Yan; Nestler, Eric J.; Hamilton, Peter J.

doi:10.1016/j.biopsych.2022.07.022

Cited by 6 publications

(4 citation statements)

References 43 publications

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“…7C). Our previously published work has shown that Zfp189 expression potentiates electrophysiological activity of nucleus accumbens neurons [21], which suggests that the spines we observe here may contribute to altered neuronal function in the PFC as well. Importantly, while ZFP189 WT and ZFP189 VPR exert opposing transcriptional regulatory control at direct ZFP189 gene targets (Fig.…”

Section: Discussionsupporting

confidence: 61%

“…We chose to control for these non-gene-regulatory consequences of viral delivery of a ZFP189 TF by using ZFP189 NFD as a control, in addition to our GFP control. Moreover, much of our prior research suggests that brain Zfp189 gene expression is experience-dependent and is activated when the animal experiences chronic social stress or drug use [7,21]. The animals in this study are naïve to these experiences, so the endogenous ZFP189 may not be highly expressed and subject to competition with the virally delivered ZFP189 TFs.…”

Section: Discussionmentioning

confidence: 99%

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A zinc finger transcription factor enables social behaviors while controlling transposable elements and immune response in prefrontal cortex

Truby,

Kim,

Silva

et al. 2024

Transl Psychiatry

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The neurobiological origins of social behaviors are incompletely understood. Here we utilized synthetic biology approaches to reprogram the function of ZFP189, a transcription factor whose expression and function in rodent prefrontal cortex was previously demonstrated to be protective against stress-induced social deficits. We created novel synthetic ZFP189 transcription factors including ZFP189VPR, which activates the transcription of target genes and therefore exerts opposite functional control from the endogenous, transcriptionally repressive ZFP189WT. Following viral delivery of these synthetic ZFP189 transcription factors to mouse prefrontal cortex, we observe that ZFP189-mediated transcriptional control promotes mature dendritic spine morphology on transduced pyramidal neurons. Interestingly, inversion of ZFP189-mediated transcription in this brain area, achieved by viral delivery of synthetic ZFP189VPR, precipitates social behavioral deficits in terms of social interaction, motivation, and the cognition necessary for the maintenance of social hierarchy, without other observable behavioral deficits. RNA sequencing of virally manipulated prefrontal cortex tissues reveals that ZFP189 transcription factors of opposing regulatory function (ZFP189WT versus ZFP189VPR) have opposite influence on the expression of genetic transposable elements as well as genes that participate in adaptive immune functions. Collectively, this work reveals that ZFP189 function in the prefrontal cortex coordinates structural and transcriptional neuroadaptations necessary for complex social behaviors while regulating transposable element-rich regions of DNA and the expression of immune-related genes. Given the evidence for a co-evolution of social behavior and the brain immune response, we posit that ZFP189 may have evolved to augment brain transposon-associated immune function as a way of enhancing an animal’s capacity for functioning in social groups.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

A zinc finger transcription factor enables social behaviors while controlling transposable elements and immune response in prefrontal cortex

Truby,

Kim,

Silva

et al. 2024

Transl Psychiatry

Self Cite

View full text Add to dashboard Cite

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“…The copyright holder for this preprint this version posted September 19, 2022. ; https://doi.org/10. 1101/2022.09.19.508525 doi: bioRxiv preprint al., 2006. Previous studies demonstrate that Egr3 is important for the induction of cellular programs of differentiation, proliferation, and cell death in response to environmental stimuli that rapidly and transiently induces its expression (Thiel and Cibelli, 2002;Unoki and Nakamura, 2003;Carter et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…In recent years, the development of epigenetic modification tools and CRISPR tools have allowed neuroscientists to alter gene expression at specific gene loci with greater specificity compared to traditional RNAi based silencing or cDNA-based overexpression (Qi et al, 2013;Heller et al, 2014Heller et al, , 2016Ran et al, 2015;Farhang et al, 2017;Klann et al, 2017;Savell et al, 2019;Duke et al, 2020;Eagle et al, 2020;Teague et al, 2022). Additionally, previous studies employed TALEs (transcription activator-like effectors) for epigenetic editing and light inducible epigenetic editing (Konermann et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Inducible CRISPR epigenome systems mimic cocaine induced bidirectional regulation of Nab2 and Egr3

Choi

Franco

Stapf

et al. 2022

Preprint

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Substance use disorder is a debilitating chronic disease and a leading cause of disability around the world. The nucleus accumbens (NAc) is a major brain hub that mediates reward behavior. Studies demonstrate exposure to cocaine is associated with molecular and functional imbalance in two NAc medium spiny neuron subtypes (MSNs), dopamine receptor 1 and 2 enriched D1-MSNs and D2-MSNs. Our previous reports showed that repeated cocaine exposure induced transcription factor early growth response 3 (Egr3) mRNA in NAc D1-MSNs, while reducing it in D2-MSNs. Here, we report our findings of repeated cocaine exposure inducing cell subtype specific bidirectional expression of the Egr3 corepressor NGFI-A-binding protein 2 (Nab2). Using CRISPR activation and interference (CRISPRa and CRISPRi) tools combined with Nab2 or Egr3 targeted sgRNAs, we mimicked these bidirectional changes in Neuro2a cells. Furthermore, we investigated D1-MSN and D2-MSN subtype specific expressional changes of histone lysine demethylases Kdm1a, Kdm6a and Kdm5c in NAc after repeated cocaine exposure. Since Kdm1a showed bidirectional expression patterns in D1-MSNs and D2-MSNs, like Egr3, we developed a light inducible Opto-CRISPR-KDM1a system. We were able to downregulate Egr3 and Nab2 transcripts and cause bidirectional expression changes in D1-MSNs and D2-MSNs similar to cocaine exposure in Neuro2A cells. In contrast, our Opto-CRISPR-p300 activation system induced the Egr3 and Nab2 transcripts and caused bidirectional transcription regulations in D1-MSNs and D2-MSNs. Our study sheds light on the expression patterns of Nab2 and Egr3 in specific NAc MSN subtypes in cocaine action and uses CRISPR tools to further mimic these expression patterns.

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Drug addiction and treatment: An epigenetic perspective

Koijam,

Singh,

Nameirakpam

et al. 2024

Biomedicine & Pharmacotherapy

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CREB Binding at the Zfp189 Promoter Within Medium Spiny Neuron Subtypes Differentially Regulates Behavioral and Physiological Adaptations Over the Course of Cocaine Use

Cited by 6 publications

References 43 publications

A zinc finger transcription factor enables social behaviors while controlling transposable elements and immune response in prefrontal cortex

A zinc finger transcription factor enables social behaviors while controlling transposable elements and immune response in prefrontal cortex

Inducible CRISPR epigenome systems mimic cocaine induced bidirectional regulation of Nab2 and Egr3

Drug addiction and treatment: An epigenetic perspective

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