Cargando…

T9. EPIGENETIC PROFILING IN SCHIZOPHRENIA DERIVED HUMAN INDUCED PLURIPOTENT STEM CELLS (HIPSCS) AND NEURONS

BACKGROUND: Schizophrenia (SCZ) is a severe psychiatric disorder affecting ~1% of the world’s population. It is largely heritable with genetic risk reflected by a combination of common variants of small effect and highly penetrant rare mutations. Chromatin modifications are known to play critical ro...

Descripción completa

Detalles Bibliográficos
Autores principales: Farrelly, Lorna, Zhang, Shuangping, Flaherty, Erin, Topol, Aaron, Schrode, Nadine, Bastle, Ryan, Bhanu, Natarajan, Garcia, Benjamin, Li, Haitao, Brennand, Kristen, Maze, Ian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233850/
http://dx.doi.org/10.1093/schbul/sbaa029.569
_version_ 1783535627401166848
author Farrelly, Lorna
Zhang, Shuangping
Flaherty, Erin
Topol, Aaron
Schrode, Nadine
Bastle, Ryan
Bhanu, Natarajan
Garcia, Benjamin
Li, Haitao
Brennand, Kristen
Maze, Ian
author_facet Farrelly, Lorna
Zhang, Shuangping
Flaherty, Erin
Topol, Aaron
Schrode, Nadine
Bastle, Ryan
Bhanu, Natarajan
Garcia, Benjamin
Li, Haitao
Brennand, Kristen
Maze, Ian
author_sort Farrelly, Lorna
collection PubMed
description BACKGROUND: Schizophrenia (SCZ) is a severe psychiatric disorder affecting ~1% of the world’s population. It is largely heritable with genetic risk reflected by a combination of common variants of small effect and highly penetrant rare mutations. Chromatin modifications are known to play critical roles in the mediation of many neurodevelopmental processes, and, when disturbed, may also contribute to the precipitation of psychiatric disorders, such as SCZ. While a handful of candidate-based studies have measured changes in promoter-bound histone modifications, few mechanistic studies have been carried out to explore how these modifications may affect chromatin to precipitate behavioral phenotypes associated with the disease. METHODS: We applied an unbiased proteomics approach to evaluate the epigenetic landscape of SCZ in human induced pluripotent stem cells (hiPSC), neural progenitor cells (NPCs) and neurons from SCZ patients vs. matched controls. We utilized proteomics-based, label free liquid chromatography mass spectrometry (LC-MS/MS) on purified histones from these cells and confirmed our results by western blotting in postmortem SCZ cortical brain tissues. Furthermore we validated our findings with the application of histone interaction assays and structural and biophysical assessments to identify and confirm novel chromatin ‘readers’. To relate our findings to a SCZ phenotype we used a SCZ rodent model of prepulse inhibition (PPI) to perform pharmacological manipulations and behavioral assessments. RESULTS: Using label free mass spectrometry we performed PTM screening of hiPSCs, NPCs and matured neurons derived from SCZ patients and matched controls. We identified, amongst others, altered patterns of hyperacetylation in SCZ neurons. Additionally we identified enhanced binding of particular acetylation ‘reader’ proteins. Pharmacological inhibition of such proteins in an animal model of amphetamine sensitization ameliorated PPI deficits further validating this epigenetic signature in SCZ. DISCUSSION: Recent evidence indicates that relevance and patterns of acetylation in epigenetics advances beyond its role in transcription and small molecule inhibitors of these aberrant interactions hold promise as useful therapeutics. This study identifies a role for modulating gene expression changes associated with a SCZ epigenetic signature and warrants further investigation in terms of how this early gene expression pattern perhaps determines susceptibility or severity of the SCZ disease trajectory.
format Online
Article
Text
id pubmed-7233850
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-72338502020-05-23 T9. EPIGENETIC PROFILING IN SCHIZOPHRENIA DERIVED HUMAN INDUCED PLURIPOTENT STEM CELLS (HIPSCS) AND NEURONS Farrelly, Lorna Zhang, Shuangping Flaherty, Erin Topol, Aaron Schrode, Nadine Bastle, Ryan Bhanu, Natarajan Garcia, Benjamin Li, Haitao Brennand, Kristen Maze, Ian Schizophr Bull Poster Session III BACKGROUND: Schizophrenia (SCZ) is a severe psychiatric disorder affecting ~1% of the world’s population. It is largely heritable with genetic risk reflected by a combination of common variants of small effect and highly penetrant rare mutations. Chromatin modifications are known to play critical roles in the mediation of many neurodevelopmental processes, and, when disturbed, may also contribute to the precipitation of psychiatric disorders, such as SCZ. While a handful of candidate-based studies have measured changes in promoter-bound histone modifications, few mechanistic studies have been carried out to explore how these modifications may affect chromatin to precipitate behavioral phenotypes associated with the disease. METHODS: We applied an unbiased proteomics approach to evaluate the epigenetic landscape of SCZ in human induced pluripotent stem cells (hiPSC), neural progenitor cells (NPCs) and neurons from SCZ patients vs. matched controls. We utilized proteomics-based, label free liquid chromatography mass spectrometry (LC-MS/MS) on purified histones from these cells and confirmed our results by western blotting in postmortem SCZ cortical brain tissues. Furthermore we validated our findings with the application of histone interaction assays and structural and biophysical assessments to identify and confirm novel chromatin ‘readers’. To relate our findings to a SCZ phenotype we used a SCZ rodent model of prepulse inhibition (PPI) to perform pharmacological manipulations and behavioral assessments. RESULTS: Using label free mass spectrometry we performed PTM screening of hiPSCs, NPCs and matured neurons derived from SCZ patients and matched controls. We identified, amongst others, altered patterns of hyperacetylation in SCZ neurons. Additionally we identified enhanced binding of particular acetylation ‘reader’ proteins. Pharmacological inhibition of such proteins in an animal model of amphetamine sensitization ameliorated PPI deficits further validating this epigenetic signature in SCZ. DISCUSSION: Recent evidence indicates that relevance and patterns of acetylation in epigenetics advances beyond its role in transcription and small molecule inhibitors of these aberrant interactions hold promise as useful therapeutics. This study identifies a role for modulating gene expression changes associated with a SCZ epigenetic signature and warrants further investigation in terms of how this early gene expression pattern perhaps determines susceptibility or severity of the SCZ disease trajectory. Oxford University Press 2020-05 2020-05-18 /pmc/articles/PMC7233850/ http://dx.doi.org/10.1093/schbul/sbaa029.569 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Poster Session III
Farrelly, Lorna
Zhang, Shuangping
Flaherty, Erin
Topol, Aaron
Schrode, Nadine
Bastle, Ryan
Bhanu, Natarajan
Garcia, Benjamin
Li, Haitao
Brennand, Kristen
Maze, Ian
T9. EPIGENETIC PROFILING IN SCHIZOPHRENIA DERIVED HUMAN INDUCED PLURIPOTENT STEM CELLS (HIPSCS) AND NEURONS
title T9. EPIGENETIC PROFILING IN SCHIZOPHRENIA DERIVED HUMAN INDUCED PLURIPOTENT STEM CELLS (HIPSCS) AND NEURONS
title_full T9. EPIGENETIC PROFILING IN SCHIZOPHRENIA DERIVED HUMAN INDUCED PLURIPOTENT STEM CELLS (HIPSCS) AND NEURONS
title_fullStr T9. EPIGENETIC PROFILING IN SCHIZOPHRENIA DERIVED HUMAN INDUCED PLURIPOTENT STEM CELLS (HIPSCS) AND NEURONS
title_full_unstemmed T9. EPIGENETIC PROFILING IN SCHIZOPHRENIA DERIVED HUMAN INDUCED PLURIPOTENT STEM CELLS (HIPSCS) AND NEURONS
title_short T9. EPIGENETIC PROFILING IN SCHIZOPHRENIA DERIVED HUMAN INDUCED PLURIPOTENT STEM CELLS (HIPSCS) AND NEURONS
title_sort t9. epigenetic profiling in schizophrenia derived human induced pluripotent stem cells (hipscs) and neurons
topic Poster Session III
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233850/
http://dx.doi.org/10.1093/schbul/sbaa029.569
work_keys_str_mv AT farrellylorna t9epigeneticprofilinginschizophreniaderivedhumaninducedpluripotentstemcellshipscsandneurons
AT zhangshuangping t9epigeneticprofilinginschizophreniaderivedhumaninducedpluripotentstemcellshipscsandneurons
AT flahertyerin t9epigeneticprofilinginschizophreniaderivedhumaninducedpluripotentstemcellshipscsandneurons
AT topolaaron t9epigeneticprofilinginschizophreniaderivedhumaninducedpluripotentstemcellshipscsandneurons
AT schrodenadine t9epigeneticprofilinginschizophreniaderivedhumaninducedpluripotentstemcellshipscsandneurons
AT bastleryan t9epigeneticprofilinginschizophreniaderivedhumaninducedpluripotentstemcellshipscsandneurons
AT bhanunatarajan t9epigeneticprofilinginschizophreniaderivedhumaninducedpluripotentstemcellshipscsandneurons
AT garciabenjamin t9epigeneticprofilinginschizophreniaderivedhumaninducedpluripotentstemcellshipscsandneurons
AT lihaitao t9epigeneticprofilinginschizophreniaderivedhumaninducedpluripotentstemcellshipscsandneurons
AT brennandkristen t9epigeneticprofilinginschizophreniaderivedhumaninducedpluripotentstemcellshipscsandneurons
AT mazeian t9epigeneticprofilinginschizophreniaderivedhumaninducedpluripotentstemcellshipscsandneurons