PMID- 31772269
OWN - NLM
STAT- MEDLINE
DCOM- 20201109
LR  - 20210110
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 9
IP  - 1
DP  - 2019 Nov 26
TI  - A framework for identification of on- and off-target transcriptional responses to 
      drug treatment.
PG  - 17603
LID - 10.1038/s41598-019-54180-4 [doi]
LID - 17603
AB  - Owing to safety concerns or insufficient efficacy, few drug candidates are 
      approved for marketing. Drugs already on the market may be withdrawn due to 
      adverse effects (AEs) discovered after market introduction. Comprehensively 
      investigating the on-/off-target effects of drugs can help expose AEs during the 
      drug development process. We have developed an integrative framework for 
      systematic identification of on-/off-target pathways and elucidation of the 
      underlying regulatory mechanisms, by combining promoter expression profiling 
      after drug treatment with gene perturbation of the primary drug target. 
      Expression profiles from statin-treated cells and HMG-CoA reductase knockdowns 
      were analyzed using the framework, allowing for identification of not only 
      reported adverse effects but also novel candidates of off-target effects from 
      statin treatment, including key regulatory elements of on- and off-targets. Our 
      findings may provide new insights for finding new usages or potential side 
      effects of drug treatment.
FAU - Huang, Yi
AU  - Huang Y
AD  - RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, 
      Japan.
FAU - Furuno, Masaaki
AU  - Furuno M
AD  - RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, 
      Japan.
FAU - Arakawa, Takahiro
AU  - Arakawa T
AD  - RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, 
      Japan.
FAU - Takizawa, Satoshi
AU  - Takizawa S
AD  - RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, 
      Japan.
FAU - de Hoon, Michiel
AU  - de Hoon M
AD  - RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, 
      Japan.
FAU - Suzuki, Harukazu
AU  - Suzuki H
AD  - RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, 
      Japan.
FAU - Arner, Erik
AU  - Arner E
AD  - RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, 
      Japan. erik.arner@riken.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Validation Study
DEP - 20191126
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (RNA, Small Interfering)
RN  - EC 1.1.1.- (HMGCR protein, human)
RN  - EC 1.1.1.- (Hydroxymethylglutaryl CoA Reductases)
SB  - IM
MH  - Algorithms
MH  - Computer Simulation
MH  - *Drug Repositioning
MH  - Gene Expression Regulation/*drug effects
MH  - Gene Knockdown Techniques
MH  - *Gene Regulatory Networks/drug effects
MH  - Hep G2 Cells
MH  - Humans
MH  - Hydroxymethylglutaryl CoA Reductases/genetics
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*adverse effects/pharmacology
MH  - MCF-7 Cells
MH  - Nucleotide Motifs
MH  - Promoter Regions, Genetic
MH  - RNA, Small Interfering/genetics
MH  - Transcription, Genetic/*drug effects
PMC - PMC6879629
COIS- The authors declare no competing interests.
EDAT- 2019/11/28 06:00
MHDA- 2020/11/11 06:00
PMCR- 2019/11/26
CRDT- 2019/11/28 06:00
PHST- 2019/09/02 00:00 [received]
PHST- 2019/11/09 00:00 [accepted]
PHST- 2019/11/28 06:00 [entrez]
PHST- 2019/11/28 06:00 [pubmed]
PHST- 2020/11/11 06:00 [medline]
PHST- 2019/11/26 00:00 [pmc-release]
AID - 10.1038/s41598-019-54180-4 [pii]
AID - 54180 [pii]
AID - 10.1038/s41598-019-54180-4 [doi]
PST - epublish
SO  - Sci Rep. 2019 Nov 26;9(1):17603. doi: 10.1038/s41598-019-54180-4.