Egr-1 induces a profibrotic injury/repair gene program associated with systemic sclerosis

Swati Bhattacharyya*, Jennifer L. Sargent, Pan Du, Simon Lin, Warren G. Tourtellotte, Kazuhiko Takehara, Michael L. Whitfield, John Varga

*Corresponding author for this work

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Transforming growth factor-ß (TGF-ß) signaling is implicated in the pathogenesis of fibrosis in scleroderma or systemic sclerosis (SSc), but the precise mechanisms are poorly understood. The immediate-early gene Egr-1 is an inducible transcription factor with key roles in mediating fibrotic TGF-ß responses. To elucidate Egr-1 function in SSc-associated fibrosis, we examined change in gene expression induced by Egr-1 in human fibroblasts at the genome-wide level. Using microarray expression analysis, we derived a fibroblast "Egr-1-responsive gene signature" comprising over 600 genes involved in cell proliferation, TGF-ß signaling, wound healing, extracellular matrix synthesis and vascular development. The experimentally derived "Egr-1-responsive gene signature" was then evaluated in an expression microarray dataset comprising skin biopsies from 27 patients with localized and systemic forms of scleroderma and six healthy controls. We found that the "Egr-1 responsive gene signature" was substantially enriched in the "diffuse-proliferation" subset comprising exclusively of patients with diffuse cutaneous SSc (dcSSc) of skin biopsies. A number of Egr-1-regulated genes was also associated with the "inflammatory" intrinsic subset. Only a minority of Egr-1-regulated genes was concordantly regulated by TGF-ß. These results indicate that Egr-1 induces a distinct profibrotic/wound healing gene expression program in fibroblasts that is associated with skin biopsies from SSc patients with diffuse cutaneous disease. These observations suggest that targeting Egr-1 expression or activity might be a novel therapeutic strategy to control fibrosis in specific SSc subsets.

Original languageEnglish (US)
Article numbere23082
JournalPloS one
Volume6
Issue number9
DOIs
StatePublished - Sep 13 2011

Fingerprint

Systemic Scleroderma
sclerosis
Repair
Genes
Transforming Growth Factors
transforming growth factors
Wounds and Injuries
Biopsy
fibrosis
skin (animal)
Fibrosis
Fibroblasts
genes
fibroblasts
biopsy
Wound Healing
Skin
tissue repair
Microarrays
Gene expression

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Bhattacharyya, Swati ; Sargent, Jennifer L. ; Du, Pan ; Lin, Simon ; Tourtellotte, Warren G. ; Takehara, Kazuhiko ; Whitfield, Michael L. ; Varga, John. / Egr-1 induces a profibrotic injury/repair gene program associated with systemic sclerosis. In: PloS one. 2011 ; Vol. 6, No. 9.
@article{7b4792fcca4d47cea97f97e149f125e4,
title = "Egr-1 induces a profibrotic injury/repair gene program associated with systemic sclerosis",
abstract = "Transforming growth factor-{\ss} (TGF-{\ss}) signaling is implicated in the pathogenesis of fibrosis in scleroderma or systemic sclerosis (SSc), but the precise mechanisms are poorly understood. The immediate-early gene Egr-1 is an inducible transcription factor with key roles in mediating fibrotic TGF-{\ss} responses. To elucidate Egr-1 function in SSc-associated fibrosis, we examined change in gene expression induced by Egr-1 in human fibroblasts at the genome-wide level. Using microarray expression analysis, we derived a fibroblast {"}Egr-1-responsive gene signature{"} comprising over 600 genes involved in cell proliferation, TGF-{\ss} signaling, wound healing, extracellular matrix synthesis and vascular development. The experimentally derived {"}Egr-1-responsive gene signature{"} was then evaluated in an expression microarray dataset comprising skin biopsies from 27 patients with localized and systemic forms of scleroderma and six healthy controls. We found that the {"}Egr-1 responsive gene signature{"} was substantially enriched in the {"}diffuse-proliferation{"} subset comprising exclusively of patients with diffuse cutaneous SSc (dcSSc) of skin biopsies. A number of Egr-1-regulated genes was also associated with the {"}inflammatory{"} intrinsic subset. Only a minority of Egr-1-regulated genes was concordantly regulated by TGF-{\ss}. These results indicate that Egr-1 induces a distinct profibrotic/wound healing gene expression program in fibroblasts that is associated with skin biopsies from SSc patients with diffuse cutaneous disease. These observations suggest that targeting Egr-1 expression or activity might be a novel therapeutic strategy to control fibrosis in specific SSc subsets.",
author = "Swati Bhattacharyya and Sargent, {Jennifer L.} and Pan Du and Simon Lin and Tourtellotte, {Warren G.} and Kazuhiko Takehara and Whitfield, {Michael L.} and John Varga",
year = "2011",
month = "9",
day = "13",
doi = "10.1371/journal.pone.0023082",
language = "English (US)",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "9",

}

Egr-1 induces a profibrotic injury/repair gene program associated with systemic sclerosis. / Bhattacharyya, Swati; Sargent, Jennifer L.; Du, Pan; Lin, Simon; Tourtellotte, Warren G.; Takehara, Kazuhiko; Whitfield, Michael L.; Varga, John.

In: PloS one, Vol. 6, No. 9, e23082, 13.09.2011.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Egr-1 induces a profibrotic injury/repair gene program associated with systemic sclerosis

AU - Bhattacharyya, Swati

AU - Sargent, Jennifer L.

AU - Du, Pan

AU - Lin, Simon

AU - Tourtellotte, Warren G.

AU - Takehara, Kazuhiko

AU - Whitfield, Michael L.

AU - Varga, John

PY - 2011/9/13

Y1 - 2011/9/13

N2 - Transforming growth factor-ß (TGF-ß) signaling is implicated in the pathogenesis of fibrosis in scleroderma or systemic sclerosis (SSc), but the precise mechanisms are poorly understood. The immediate-early gene Egr-1 is an inducible transcription factor with key roles in mediating fibrotic TGF-ß responses. To elucidate Egr-1 function in SSc-associated fibrosis, we examined change in gene expression induced by Egr-1 in human fibroblasts at the genome-wide level. Using microarray expression analysis, we derived a fibroblast "Egr-1-responsive gene signature" comprising over 600 genes involved in cell proliferation, TGF-ß signaling, wound healing, extracellular matrix synthesis and vascular development. The experimentally derived "Egr-1-responsive gene signature" was then evaluated in an expression microarray dataset comprising skin biopsies from 27 patients with localized and systemic forms of scleroderma and six healthy controls. We found that the "Egr-1 responsive gene signature" was substantially enriched in the "diffuse-proliferation" subset comprising exclusively of patients with diffuse cutaneous SSc (dcSSc) of skin biopsies. A number of Egr-1-regulated genes was also associated with the "inflammatory" intrinsic subset. Only a minority of Egr-1-regulated genes was concordantly regulated by TGF-ß. These results indicate that Egr-1 induces a distinct profibrotic/wound healing gene expression program in fibroblasts that is associated with skin biopsies from SSc patients with diffuse cutaneous disease. These observations suggest that targeting Egr-1 expression or activity might be a novel therapeutic strategy to control fibrosis in specific SSc subsets.

AB - Transforming growth factor-ß (TGF-ß) signaling is implicated in the pathogenesis of fibrosis in scleroderma or systemic sclerosis (SSc), but the precise mechanisms are poorly understood. The immediate-early gene Egr-1 is an inducible transcription factor with key roles in mediating fibrotic TGF-ß responses. To elucidate Egr-1 function in SSc-associated fibrosis, we examined change in gene expression induced by Egr-1 in human fibroblasts at the genome-wide level. Using microarray expression analysis, we derived a fibroblast "Egr-1-responsive gene signature" comprising over 600 genes involved in cell proliferation, TGF-ß signaling, wound healing, extracellular matrix synthesis and vascular development. The experimentally derived "Egr-1-responsive gene signature" was then evaluated in an expression microarray dataset comprising skin biopsies from 27 patients with localized and systemic forms of scleroderma and six healthy controls. We found that the "Egr-1 responsive gene signature" was substantially enriched in the "diffuse-proliferation" subset comprising exclusively of patients with diffuse cutaneous SSc (dcSSc) of skin biopsies. A number of Egr-1-regulated genes was also associated with the "inflammatory" intrinsic subset. Only a minority of Egr-1-regulated genes was concordantly regulated by TGF-ß. These results indicate that Egr-1 induces a distinct profibrotic/wound healing gene expression program in fibroblasts that is associated with skin biopsies from SSc patients with diffuse cutaneous disease. These observations suggest that targeting Egr-1 expression or activity might be a novel therapeutic strategy to control fibrosis in specific SSc subsets.

UR - http://www.scopus.com/inward/record.url?scp=80052715015&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052715015&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0023082

DO - 10.1371/journal.pone.0023082

M3 - Article

C2 - 21931594

AN - SCOPUS:80052715015

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 9

M1 - e23082

ER -