EZH1 is an antipsychotic-sensitive epigenetic modulator of social and motivational behavior that is dysregulated in schizophrenia

Andrea L. Johnstone, Jiaqi J. O'Reilly, Annika J. Patel, Zhihong Guo, Nadja S. Andrade, Marco Magistri, Lubov Nathanson, Rustam Esanov, Brooke H. Miller, Gustavo Turecki, Shaun P Brothers, Zane R Zeier, Claes R Wahlestedt

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: With the capacity to modulate gene networks in an environmentally-sensitive manner, the role of epigenetic systems in mental disorders has come under intense investigation. Dysregulation of epigenetic effectors, including microRNAs and histone-modifying enzymes, may better explain the role of environmental risk factors and the observed heritability rate that cannot be fully attributed to known genetic risk alleles. Here, we aimed to identify novel epigenetic targets of the schizophrenia-associated microRNA 132 (miR-132). Methods: Histone modifications were quantified by immunodetection in response to viral-mediated overexpression of miR-132 while a luminescent reporter system was used to validate targets of miR-132 in vitro. Genome-wide profiling, quantitative PCR and NanoSting were used to quantify gene expression in post-mortem human brains, neuronal cultures and prefrontal cortex (PFC) of mice chronically exposed to antipsychotics. Following viral-mediated depletion of Enhancer of Zeste 1 (EZH1) in the murine PFC, behaviors including sociability and motivation were assessed using a 3-chambered apparatus and forced-swim test, respectively. Results: Overexpression of miR-132 decreased global histone 3 lysine 27 tri-methylation (H3K27me3), a repressive epigenetic mark. Moreover, the polycomb-associated H3K27 methyltransferase, EZH1, is regulated by miR-132 and upregulated in the PFC of schizophrenics. Unlike its homolog EZH2, expression of EZH1 in the murine PFC decreased following chronic exposure to antipsychotics. Viral-mediated depletion of EZH1 in the mouse PFC attenuated sociability, enhanced motivational behaviors, and affected gene expression pathways related to neurotransmission and behavioral phenotypes. Conclusions: EZH1 is dysregulated in schizophrenia, sensitive to antipsychotic medications, and a brain-enriched miR-132 target that controls neurobehavioral phenotypes.

Original languageEnglish (US)
Pages (from-to)149-158
Number of pages10
JournalNeurobiology of Disease
Volume119
DOIs
StatePublished - Nov 1 2018

Fingerprint

MicroRNAs
Epigenomics
Antipsychotic Agents
Schizophrenia
Prefrontal Cortex
Histones
Histone Code
Phenotype
Gene Expression
Gene Regulatory Networks
Brain
Methyltransferases
Mental Disorders
Synaptic Transmission
Methylation
Lysine
Motivation
Alleles
Genome
Polymerase Chain Reaction

Keywords

  • Antipsychotics
  • Epigenetics
  • miR-132, EZH1, microRNA
  • Prefrontal cortex
  • Schizophrenia

ASJC Scopus subject areas

  • Neurology

Cite this

EZH1 is an antipsychotic-sensitive epigenetic modulator of social and motivational behavior that is dysregulated in schizophrenia. / Johnstone, Andrea L.; O'Reilly, Jiaqi J.; Patel, Annika J.; Guo, Zhihong; Andrade, Nadja S.; Magistri, Marco; Nathanson, Lubov; Esanov, Rustam; Miller, Brooke H.; Turecki, Gustavo; Brothers, Shaun P; Zeier, Zane R; Wahlestedt, Claes R.

In: Neurobiology of Disease, Vol. 119, 01.11.2018, p. 149-158.

Research output: Contribution to journalArticle

Johnstone, AL, O'Reilly, JJ, Patel, AJ, Guo, Z, Andrade, NS, Magistri, M, Nathanson, L, Esanov, R, Miller, BH, Turecki, G, Brothers, SP, Zeier, ZR & Wahlestedt, CR 2018, 'EZH1 is an antipsychotic-sensitive epigenetic modulator of social and motivational behavior that is dysregulated in schizophrenia', Neurobiology of Disease, vol. 119, pp. 149-158. https://doi.org/10.1016/j.nbd.2018.08.005
Johnstone, Andrea L. ; O'Reilly, Jiaqi J. ; Patel, Annika J. ; Guo, Zhihong ; Andrade, Nadja S. ; Magistri, Marco ; Nathanson, Lubov ; Esanov, Rustam ; Miller, Brooke H. ; Turecki, Gustavo ; Brothers, Shaun P ; Zeier, Zane R ; Wahlestedt, Claes R. / EZH1 is an antipsychotic-sensitive epigenetic modulator of social and motivational behavior that is dysregulated in schizophrenia. In: Neurobiology of Disease. 2018 ; Vol. 119. pp. 149-158.
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title = "EZH1 is an antipsychotic-sensitive epigenetic modulator of social and motivational behavior that is dysregulated in schizophrenia",
abstract = "Background: With the capacity to modulate gene networks in an environmentally-sensitive manner, the role of epigenetic systems in mental disorders has come under intense investigation. Dysregulation of epigenetic effectors, including microRNAs and histone-modifying enzymes, may better explain the role of environmental risk factors and the observed heritability rate that cannot be fully attributed to known genetic risk alleles. Here, we aimed to identify novel epigenetic targets of the schizophrenia-associated microRNA 132 (miR-132). Methods: Histone modifications were quantified by immunodetection in response to viral-mediated overexpression of miR-132 while a luminescent reporter system was used to validate targets of miR-132 in vitro. Genome-wide profiling, quantitative PCR and NanoSting were used to quantify gene expression in post-mortem human brains, neuronal cultures and prefrontal cortex (PFC) of mice chronically exposed to antipsychotics. Following viral-mediated depletion of Enhancer of Zeste 1 (EZH1) in the murine PFC, behaviors including sociability and motivation were assessed using a 3-chambered apparatus and forced-swim test, respectively. Results: Overexpression of miR-132 decreased global histone 3 lysine 27 tri-methylation (H3K27me3), a repressive epigenetic mark. Moreover, the polycomb-associated H3K27 methyltransferase, EZH1, is regulated by miR-132 and upregulated in the PFC of schizophrenics. Unlike its homolog EZH2, expression of EZH1 in the murine PFC decreased following chronic exposure to antipsychotics. Viral-mediated depletion of EZH1 in the mouse PFC attenuated sociability, enhanced motivational behaviors, and affected gene expression pathways related to neurotransmission and behavioral phenotypes. Conclusions: EZH1 is dysregulated in schizophrenia, sensitive to antipsychotic medications, and a brain-enriched miR-132 target that controls neurobehavioral phenotypes.",
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T1 - EZH1 is an antipsychotic-sensitive epigenetic modulator of social and motivational behavior that is dysregulated in schizophrenia

AU - Johnstone, Andrea L.

AU - O'Reilly, Jiaqi J.

AU - Patel, Annika J.

AU - Guo, Zhihong

AU - Andrade, Nadja S.

AU - Magistri, Marco

AU - Nathanson, Lubov

AU - Esanov, Rustam

AU - Miller, Brooke H.

AU - Turecki, Gustavo

AU - Brothers, Shaun P

AU - Zeier, Zane R

AU - Wahlestedt, Claes R

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Background: With the capacity to modulate gene networks in an environmentally-sensitive manner, the role of epigenetic systems in mental disorders has come under intense investigation. Dysregulation of epigenetic effectors, including microRNAs and histone-modifying enzymes, may better explain the role of environmental risk factors and the observed heritability rate that cannot be fully attributed to known genetic risk alleles. Here, we aimed to identify novel epigenetic targets of the schizophrenia-associated microRNA 132 (miR-132). Methods: Histone modifications were quantified by immunodetection in response to viral-mediated overexpression of miR-132 while a luminescent reporter system was used to validate targets of miR-132 in vitro. Genome-wide profiling, quantitative PCR and NanoSting were used to quantify gene expression in post-mortem human brains, neuronal cultures and prefrontal cortex (PFC) of mice chronically exposed to antipsychotics. Following viral-mediated depletion of Enhancer of Zeste 1 (EZH1) in the murine PFC, behaviors including sociability and motivation were assessed using a 3-chambered apparatus and forced-swim test, respectively. Results: Overexpression of miR-132 decreased global histone 3 lysine 27 tri-methylation (H3K27me3), a repressive epigenetic mark. Moreover, the polycomb-associated H3K27 methyltransferase, EZH1, is regulated by miR-132 and upregulated in the PFC of schizophrenics. Unlike its homolog EZH2, expression of EZH1 in the murine PFC decreased following chronic exposure to antipsychotics. Viral-mediated depletion of EZH1 in the mouse PFC attenuated sociability, enhanced motivational behaviors, and affected gene expression pathways related to neurotransmission and behavioral phenotypes. Conclusions: EZH1 is dysregulated in schizophrenia, sensitive to antipsychotic medications, and a brain-enriched miR-132 target that controls neurobehavioral phenotypes.

AB - Background: With the capacity to modulate gene networks in an environmentally-sensitive manner, the role of epigenetic systems in mental disorders has come under intense investigation. Dysregulation of epigenetic effectors, including microRNAs and histone-modifying enzymes, may better explain the role of environmental risk factors and the observed heritability rate that cannot be fully attributed to known genetic risk alleles. Here, we aimed to identify novel epigenetic targets of the schizophrenia-associated microRNA 132 (miR-132). Methods: Histone modifications were quantified by immunodetection in response to viral-mediated overexpression of miR-132 while a luminescent reporter system was used to validate targets of miR-132 in vitro. Genome-wide profiling, quantitative PCR and NanoSting were used to quantify gene expression in post-mortem human brains, neuronal cultures and prefrontal cortex (PFC) of mice chronically exposed to antipsychotics. Following viral-mediated depletion of Enhancer of Zeste 1 (EZH1) in the murine PFC, behaviors including sociability and motivation were assessed using a 3-chambered apparatus and forced-swim test, respectively. Results: Overexpression of miR-132 decreased global histone 3 lysine 27 tri-methylation (H3K27me3), a repressive epigenetic mark. Moreover, the polycomb-associated H3K27 methyltransferase, EZH1, is regulated by miR-132 and upregulated in the PFC of schizophrenics. Unlike its homolog EZH2, expression of EZH1 in the murine PFC decreased following chronic exposure to antipsychotics. Viral-mediated depletion of EZH1 in the mouse PFC attenuated sociability, enhanced motivational behaviors, and affected gene expression pathways related to neurotransmission and behavioral phenotypes. Conclusions: EZH1 is dysregulated in schizophrenia, sensitive to antipsychotic medications, and a brain-enriched miR-132 target that controls neurobehavioral phenotypes.

KW - Antipsychotics

KW - Epigenetics

KW - miR-132, EZH1, microRNA

KW - Prefrontal cortex

KW - Schizophrenia

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