Improving drug discovery using image-based multiparametric analysis of the epigenetic landscape.
Antineoplastic Agents
/ therapeutic use
Biomarkers, Tumor
/ genetics
Brain Neoplasms
/ drug therapy
Cell Line, Tumor
Cell Nucleus
/ drug effects
Dose-Response Relationship, Drug
Drug Discovery
/ methods
Epigenesis, Genetic
/ drug effects
Glioblastoma
/ drug therapy
High-Throughput Screening Assays
Histones
/ genetics
Humans
Image Processing, Computer-Assisted
/ statistics & numerical data
Machine Learning
Microscopy, Fluorescence
Neoplasm Proteins
/ genetics
cancer biology
epigenetics
glioblastoma
high content screening
human
human biology
medicine
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
22 10 2019
22 10 2019
Historique:
received:
27
06
2019
accepted:
05
10
2019
pubmed:
23
10
2019
medline:
10
5
2020
entrez:
23
10
2019
Statut:
epublish
Résumé
High-content phenotypic screening has become the approach of choice for drug discovery due to its ability to extract drug-specific multi-layered data. In the field of epigenetics, such screening methods have suffered from a lack of tools sensitive to selective epigenetic perturbations. Here we describe a novel approach, Microscopic Imaging of Epigenetic Landscapes (MIEL), which captures the nuclear staining patterns of epigenetic marks and employs machine learning to accurately distinguish between such patterns. We validated the MIEL platform across multiple cells lines and using dose-response curves, to insure the fidelity and robustness of this approach for high content high throughput drug discovery. Focusing on noncytotoxic glioblastoma treatments, we demonstrated that MIEL can identify and classify epigenetically active drugs. Furthermore, we show MIEL was able to accurately rank candidate drugs by their ability to produce desired epigenetic alterations consistent with increased sensitivity to chemotherapeutic agents or with induction of glioblastoma differentiation.
Identifiants
pubmed: 31637999
doi: 10.7554/eLife.49683
pii: 49683
pmc: PMC6908434
doi:
pii:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Tumor
0
Histones
0
Neoplasm Proteins
0
Banques de données
GEO
['GSE134045']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Canada Research Chairs
ID : Tier 1 Canada Research Chair
Pays : International
Organisme : NHLBI NIH HHS
ID : R01 HL115158
Pays : United States
Organisme : California Institute for Regenerative Medicine
ID : TG2-01162
Pays : International
Organisme : NIH HHS
ID : R01 NS066278
Pays : United States
Organisme : Celgene
ID : SCRA
Pays : International
Informations de copyright
© 2019, Farhy et al.
Déclaration de conflit d'intérêts
CF, SH, JY, LO, FZ, IP, FU, EF, CH, DA, AT No competing interests declared
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