A map of the PPARα transcription regulatory network for primary human hepatocytes

Patrick D. McMullen, Sudin Bhattacharya, Courtney G. Woods, Bin Sun, Kathy Yarborough, Susan M. Ross, Manda E. Miller, Mary T. McBride, Edward L. Lecluyse, Rebecca A. Clewell, Melvin E. Andersen

Research output: Research - peer-reviewArticle

  • 36 Citations

Abstract

Nuclear receptor activation in liver leads to coordinated alteration of the expression of multiple gene products with attendant phenotypic changes of hepatocytes. Peroxisome proliferators including endogenous fatty acids, environmental chemicals, and drugs induce a multi-enzyme metabolic response that affects lipid and fatty acid processing. We studied the signaling network for the peroxisome proliferator-associated receptor alpha (PPARα) in primary human hepatocytes using the selective PPARα ligand, GW7647. We measured gene expression over multiple concentrations and times and conducted ChIP-seq studies at 2 and 24 h to assess genomic binding of PPARα. Over all treatments there were 192 genes differentially expressed. Of these only 51% showed evidence of PPARα binding-either directly at PPARα response elements or via alternative mechanisms. Almost half of regulated genes had no PPARα binding. We then developed two novel bioinformatics methods to visualize the dose-dependent activation of both the transcription factor circuitry for PPARα and the downstream metabolic network in relation to functional annotation categories. Available databases identified several key transcription factors involved with the non-genomic targets after GW7647 treatment, including SP1, STAT1, ETS1, ERα, and HNF4α. The linkage from PPARα binding through gene expression likely requires intermediate protein kinases to activate these transcription factors. We found enrichment of functional annotation categories for organic acid metabolism and cell lipid metabolism among the differentially expressed genes. Lipid transport processes showed enrichment at the highest concentration of GW7647 (10 μM). While our strategy for mapping transcriptional networks is evolving, these approaches are necessary in moving from toxicogenomic methods that derive signatures of activity to methods that establish pathway structure, showing the coordination of the activated nuclear receptor with other signaling pathways.

LanguageEnglish (US)
Pages14-24
Number of pages11
JournalChemico-Biological Interactions
Volume209
Issue number1
DOIs
StatePublished - Feb 25 2014
Externally publishedYes

Profile

Hepatocytes
Transcription Factors
Gene Expression
Genes
GW 7647
Transcription
Peroxisome Proliferators
Cytoplasmic and Nuclear Receptors
Fatty Acids
Lipids
Gene expression
Chemical activation
Toxicogenetics
Gene Regulatory Networks
Response Elements
Metabolic Networks and Pathways
Computational Biology
Lipid Metabolism
Protein Kinases
Databases

Keywords

  • High-throughput technologies
  • Toxicity pathways
  • TT21C

ASJC Scopus subject areas

  • Toxicology

Cite this

McMullen, P. D., Bhattacharya, S., Woods, C. G., Sun, B., Yarborough, K., Ross, S. M., ... Andersen, M. E. (2014). A map of the PPARα transcription regulatory network for primary human hepatocytes. Chemico-Biological Interactions, 209(1), 14-24. DOI: 10.1016/j.cbi.2013.11.006

A map of the PPARα transcription regulatory network for primary human hepatocytes. / McMullen, Patrick D.; Bhattacharya, Sudin; Woods, Courtney G.; Sun, Bin; Yarborough, Kathy; Ross, Susan M.; Miller, Manda E.; McBride, Mary T.; Lecluyse, Edward L.; Clewell, Rebecca A.; Andersen, Melvin E.

In: Chemico-Biological Interactions, Vol. 209, No. 1, 25.02.2014, p. 14-24.

Research output: Research - peer-reviewArticle

McMullen, PD, Bhattacharya, S, Woods, CG, Sun, B, Yarborough, K, Ross, SM, Miller, ME, McBride, MT, Lecluyse, EL, Clewell, RA & Andersen, ME 2014, 'A map of the PPARα transcription regulatory network for primary human hepatocytes' Chemico-Biological Interactions, vol 209, no. 1, pp. 14-24. DOI: 10.1016/j.cbi.2013.11.006
McMullen PD, Bhattacharya S, Woods CG, Sun B, Yarborough K, Ross SM et al. A map of the PPARα transcription regulatory network for primary human hepatocytes. Chemico-Biological Interactions. 2014 Feb 25;209(1):14-24. Available from, DOI: 10.1016/j.cbi.2013.11.006
McMullen, Patrick D. ; Bhattacharya, Sudin ; Woods, Courtney G. ; Sun, Bin ; Yarborough, Kathy ; Ross, Susan M. ; Miller, Manda E. ; McBride, Mary T. ; Lecluyse, Edward L. ; Clewell, Rebecca A. ; Andersen, Melvin E./ A map of the PPARα transcription regulatory network for primary human hepatocytes. In: Chemico-Biological Interactions. 2014 ; Vol. 209, No. 1. pp. 14-24
@article{62f8d50816b24d4381acc5b02fd94c57,
title = "A map of the PPARα transcription regulatory network for primary human hepatocytes",
abstract = "Nuclear receptor activation in liver leads to coordinated alteration of the expression of multiple gene products with attendant phenotypic changes of hepatocytes. Peroxisome proliferators including endogenous fatty acids, environmental chemicals, and drugs induce a multi-enzyme metabolic response that affects lipid and fatty acid processing. We studied the signaling network for the peroxisome proliferator-associated receptor alpha (PPARα) in primary human hepatocytes using the selective PPARα ligand, GW7647. We measured gene expression over multiple concentrations and times and conducted ChIP-seq studies at 2 and 24 h to assess genomic binding of PPARα. Over all treatments there were 192 genes differentially expressed. Of these only 51% showed evidence of PPARα binding-either directly at PPARα response elements or via alternative mechanisms. Almost half of regulated genes had no PPARα binding. We then developed two novel bioinformatics methods to visualize the dose-dependent activation of both the transcription factor circuitry for PPARα and the downstream metabolic network in relation to functional annotation categories. Available databases identified several key transcription factors involved with the non-genomic targets after GW7647 treatment, including SP1, STAT1, ETS1, ERα, and HNF4α. The linkage from PPARα binding through gene expression likely requires intermediate protein kinases to activate these transcription factors. We found enrichment of functional annotation categories for organic acid metabolism and cell lipid metabolism among the differentially expressed genes. Lipid transport processes showed enrichment at the highest concentration of GW7647 (10 μM). While our strategy for mapping transcriptional networks is evolving, these approaches are necessary in moving from toxicogenomic methods that derive signatures of activity to methods that establish pathway structure, showing the coordination of the activated nuclear receptor with other signaling pathways.",
keywords = "High-throughput technologies, Toxicity pathways, TT21C",
author = "McMullen, {Patrick D.} and Sudin Bhattacharya and Woods, {Courtney G.} and Bin Sun and Kathy Yarborough and Ross, {Susan M.} and Miller, {Manda E.} and McBride, {Mary T.} and Lecluyse, {Edward L.} and Clewell, {Rebecca A.} and Andersen, {Melvin E.}",
year = "2014",
month = "2",
doi = "10.1016/j.cbi.2013.11.006",
volume = "209",
pages = "14--24",
journal = "Chemico-Biological Interactions",
issn = "0009-2797",
publisher = "Elsevier Ireland Ltd",
number = "1",

}

TY - JOUR

T1 - A map of the PPARα transcription regulatory network for primary human hepatocytes

AU - McMullen,Patrick D.

AU - Bhattacharya,Sudin

AU - Woods,Courtney G.

AU - Sun,Bin

AU - Yarborough,Kathy

AU - Ross,Susan M.

AU - Miller,Manda E.

AU - McBride,Mary T.

AU - Lecluyse,Edward L.

AU - Clewell,Rebecca A.

AU - Andersen,Melvin E.

PY - 2014/2/25

Y1 - 2014/2/25

N2 - Nuclear receptor activation in liver leads to coordinated alteration of the expression of multiple gene products with attendant phenotypic changes of hepatocytes. Peroxisome proliferators including endogenous fatty acids, environmental chemicals, and drugs induce a multi-enzyme metabolic response that affects lipid and fatty acid processing. We studied the signaling network for the peroxisome proliferator-associated receptor alpha (PPARα) in primary human hepatocytes using the selective PPARα ligand, GW7647. We measured gene expression over multiple concentrations and times and conducted ChIP-seq studies at 2 and 24 h to assess genomic binding of PPARα. Over all treatments there were 192 genes differentially expressed. Of these only 51% showed evidence of PPARα binding-either directly at PPARα response elements or via alternative mechanisms. Almost half of regulated genes had no PPARα binding. We then developed two novel bioinformatics methods to visualize the dose-dependent activation of both the transcription factor circuitry for PPARα and the downstream metabolic network in relation to functional annotation categories. Available databases identified several key transcription factors involved with the non-genomic targets after GW7647 treatment, including SP1, STAT1, ETS1, ERα, and HNF4α. The linkage from PPARα binding through gene expression likely requires intermediate protein kinases to activate these transcription factors. We found enrichment of functional annotation categories for organic acid metabolism and cell lipid metabolism among the differentially expressed genes. Lipid transport processes showed enrichment at the highest concentration of GW7647 (10 μM). While our strategy for mapping transcriptional networks is evolving, these approaches are necessary in moving from toxicogenomic methods that derive signatures of activity to methods that establish pathway structure, showing the coordination of the activated nuclear receptor with other signaling pathways.

AB - Nuclear receptor activation in liver leads to coordinated alteration of the expression of multiple gene products with attendant phenotypic changes of hepatocytes. Peroxisome proliferators including endogenous fatty acids, environmental chemicals, and drugs induce a multi-enzyme metabolic response that affects lipid and fatty acid processing. We studied the signaling network for the peroxisome proliferator-associated receptor alpha (PPARα) in primary human hepatocytes using the selective PPARα ligand, GW7647. We measured gene expression over multiple concentrations and times and conducted ChIP-seq studies at 2 and 24 h to assess genomic binding of PPARα. Over all treatments there were 192 genes differentially expressed. Of these only 51% showed evidence of PPARα binding-either directly at PPARα response elements or via alternative mechanisms. Almost half of regulated genes had no PPARα binding. We then developed two novel bioinformatics methods to visualize the dose-dependent activation of both the transcription factor circuitry for PPARα and the downstream metabolic network in relation to functional annotation categories. Available databases identified several key transcription factors involved with the non-genomic targets after GW7647 treatment, including SP1, STAT1, ETS1, ERα, and HNF4α. The linkage from PPARα binding through gene expression likely requires intermediate protein kinases to activate these transcription factors. We found enrichment of functional annotation categories for organic acid metabolism and cell lipid metabolism among the differentially expressed genes. Lipid transport processes showed enrichment at the highest concentration of GW7647 (10 μM). While our strategy for mapping transcriptional networks is evolving, these approaches are necessary in moving from toxicogenomic methods that derive signatures of activity to methods that establish pathway structure, showing the coordination of the activated nuclear receptor with other signaling pathways.

KW - High-throughput technologies

KW - Toxicity pathways

KW - TT21C

UR - http://www.scopus.com/inward/record.url?scp=84891514922&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84891514922&partnerID=8YFLogxK

U2 - 10.1016/j.cbi.2013.11.006

DO - 10.1016/j.cbi.2013.11.006

M3 - Article

VL - 209

SP - 14

EP - 24

JO - Chemico-Biological Interactions

T2 - Chemico-Biological Interactions

JF - Chemico-Biological Interactions

SN - 0009-2797

IS - 1

ER -