Limits...
AP-1 mediated transcriptional repression of matrix metalloproteinase-9 by recruitment of histone deacetylase 1 in response to interferon β.

Mittelstadt ML, Patel RC - PLoS ONE (2012)

Bottom Line: Using reporter assays with promoter deletion constructs we show that IFNβ's inhibitory effects require a region of the promoter between -154 and -72, which contains an AP-1 binding site.Chromatin immunoprecipitation (ChIP) studies indicate that IFNβ increases histone deacetylase (HDAC)-1 recruitment to the MMP-9 promoter and reduces histone H3 acetylation, in addition to reduced NF-κB recruitment.Altogether, our results establish that the repression of MMP-9 transcription in response to IFNβ occurs by the recruitment of HDAC1 via the proximal AP-1 binding site.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, University of South Carolina, Columbia, South Carolina, United States of America.

ABSTRACT
Matrix metalloproteinase-9 (MMP-9) is a 92 kDa zinc-dependant endopeptidase that degrades components of the extracellular matrix. Increased expression of MMP-9 is implicated in many pathological conditions including metastatic cancer, multiple sclerosis, and atherosclerosis. Although it has been widely noted that interferon-β (IFNβ) downregulates both the basal and phorbol 12-myristate 13-acetate (PMA)-induced MMP-9 expression at the transcriptional level, the molecular mechanism of this repression is poorly understood. In the present study we identify a novel mechanism for repression of MMP-9 transcription by IFNβ in HT1080 fibrosarcoma cells. Using reporter assays with promoter deletion constructs we show that IFNβ's inhibitory effects require a region of the promoter between -154 and -72, which contains an AP-1 binding site. Chromatin immunoprecipitation (ChIP) studies indicate that IFNβ increases histone deacetylase (HDAC)-1 recruitment to the MMP-9 promoter and reduces histone H3 acetylation, in addition to reduced NF-κB recruitment. ChIP analysis shows that IFNβ induced HDAC1 recruitment to the MMP-9 promoter and IFNβ mediated transcriptional repression is lost when the AP-1 binding site is inactivated by a point mutation. Altogether, our results establish that the repression of MMP-9 transcription in response to IFNβ occurs by the recruitment of HDAC1 via the proximal AP-1 binding site.

Show MeSH

Related in: MedlinePlus

AP-1-mediated recruitment of HDAC1 to MMP-9 promoter in response to IFNβ - a schematic model.Based on our results and some of the previously published work [18], this model indicates what is occurring at the MMP-9 promoter under IFNβ treatment conditions. (A) Under uninduced conditions, there is a basal level of HDAC1 and general transcription factor occupation of the MMP-9 promoter. (B) Upon PMA treatment, recruitment of specific transcription factors NF-κB, AP-1, and Sp1 occurs and MMP-9 transcription is induced. Coactivators are also recruited, such as p300, which results in acetylation of the lysine tails of histones. (C) IFNβ treatment causes HDAC1 to be recruited to the proximal AP-1 site and a corresponding decrease in local acetylation, leading to decreased transcriptional activation of MMP-9. While AP-1 occupation of the MMP-9 promoter is unchanged under IFNβ treatment, NF-κB and other specific activators leave the promoter.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3412826&req=5

pone-0042152-g005: AP-1-mediated recruitment of HDAC1 to MMP-9 promoter in response to IFNβ - a schematic model.Based on our results and some of the previously published work [18], this model indicates what is occurring at the MMP-9 promoter under IFNβ treatment conditions. (A) Under uninduced conditions, there is a basal level of HDAC1 and general transcription factor occupation of the MMP-9 promoter. (B) Upon PMA treatment, recruitment of specific transcription factors NF-κB, AP-1, and Sp1 occurs and MMP-9 transcription is induced. Coactivators are also recruited, such as p300, which results in acetylation of the lysine tails of histones. (C) IFNβ treatment causes HDAC1 to be recruited to the proximal AP-1 site and a corresponding decrease in local acetylation, leading to decreased transcriptional activation of MMP-9. While AP-1 occupation of the MMP-9 promoter is unchanged under IFNβ treatment, NF-κB and other specific activators leave the promoter.

Mentions: Our results describe a mechanism whereby transcription factor AP-1 acts to downregulate transcription of MMP-9 gene in contrast to its usual role as a transcription factor. Based on our results and previously published work [18] we propose a model for the mechanism of IFNβ mediated transcriptional downregulation of MMP-9 promoter. Under uninduced conditions, general transcription factors occupy the MMP-9 promoter along with HDAC1, contributing to a tight chromatin structure which excludes RNA polymerase binding (Figure 5, panel A). Under induced conditions NF-κB, AP-1, other cis-acting transcription factors, and co-activators such as p300 are recruited to the MMP-9 promoter. There is an increased local histone acetylation, which confers a loose chromatin structure, binding of RNA polymerase and high transcriptional activation of MMP-9 (Figure 5, panel B). Under IFNβ treatment conditions, NF-κB occupation of the MMP-9 promoter is decreased and HDAC1 is recruited via the proximal AP-1 site to the MMP-9 promoter. The DNA binding of AP-1 is unchanged under IFNβ treatment (Figure 5, panel C). We propose that the recruitment of HDAC1 on MMP-9 promoter occurs via interaction with the AP-1 transcription factor, and that certain posttranslational modification(s) of AP-1 that occurs in response to IFNβ mediates this interaction. Consequently, there is a decreased local histone acetylation after IFNβ exposure, which confers a more tightly packed chromatin structure and may result in reduced transcription of MMP-9.


AP-1 mediated transcriptional repression of matrix metalloproteinase-9 by recruitment of histone deacetylase 1 in response to interferon β.

Mittelstadt ML, Patel RC - PLoS ONE (2012)

AP-1-mediated recruitment of HDAC1 to MMP-9 promoter in response to IFNβ - a schematic model.Based on our results and some of the previously published work [18], this model indicates what is occurring at the MMP-9 promoter under IFNβ treatment conditions. (A) Under uninduced conditions, there is a basal level of HDAC1 and general transcription factor occupation of the MMP-9 promoter. (B) Upon PMA treatment, recruitment of specific transcription factors NF-κB, AP-1, and Sp1 occurs and MMP-9 transcription is induced. Coactivators are also recruited, such as p300, which results in acetylation of the lysine tails of histones. (C) IFNβ treatment causes HDAC1 to be recruited to the proximal AP-1 site and a corresponding decrease in local acetylation, leading to decreased transcriptional activation of MMP-9. While AP-1 occupation of the MMP-9 promoter is unchanged under IFNβ treatment, NF-κB and other specific activators leave the promoter.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3412826&req=5

pone-0042152-g005: AP-1-mediated recruitment of HDAC1 to MMP-9 promoter in response to IFNβ - a schematic model.Based on our results and some of the previously published work [18], this model indicates what is occurring at the MMP-9 promoter under IFNβ treatment conditions. (A) Under uninduced conditions, there is a basal level of HDAC1 and general transcription factor occupation of the MMP-9 promoter. (B) Upon PMA treatment, recruitment of specific transcription factors NF-κB, AP-1, and Sp1 occurs and MMP-9 transcription is induced. Coactivators are also recruited, such as p300, which results in acetylation of the lysine tails of histones. (C) IFNβ treatment causes HDAC1 to be recruited to the proximal AP-1 site and a corresponding decrease in local acetylation, leading to decreased transcriptional activation of MMP-9. While AP-1 occupation of the MMP-9 promoter is unchanged under IFNβ treatment, NF-κB and other specific activators leave the promoter.
Mentions: Our results describe a mechanism whereby transcription factor AP-1 acts to downregulate transcription of MMP-9 gene in contrast to its usual role as a transcription factor. Based on our results and previously published work [18] we propose a model for the mechanism of IFNβ mediated transcriptional downregulation of MMP-9 promoter. Under uninduced conditions, general transcription factors occupy the MMP-9 promoter along with HDAC1, contributing to a tight chromatin structure which excludes RNA polymerase binding (Figure 5, panel A). Under induced conditions NF-κB, AP-1, other cis-acting transcription factors, and co-activators such as p300 are recruited to the MMP-9 promoter. There is an increased local histone acetylation, which confers a loose chromatin structure, binding of RNA polymerase and high transcriptional activation of MMP-9 (Figure 5, panel B). Under IFNβ treatment conditions, NF-κB occupation of the MMP-9 promoter is decreased and HDAC1 is recruited via the proximal AP-1 site to the MMP-9 promoter. The DNA binding of AP-1 is unchanged under IFNβ treatment (Figure 5, panel C). We propose that the recruitment of HDAC1 on MMP-9 promoter occurs via interaction with the AP-1 transcription factor, and that certain posttranslational modification(s) of AP-1 that occurs in response to IFNβ mediates this interaction. Consequently, there is a decreased local histone acetylation after IFNβ exposure, which confers a more tightly packed chromatin structure and may result in reduced transcription of MMP-9.

Bottom Line: Using reporter assays with promoter deletion constructs we show that IFNβ's inhibitory effects require a region of the promoter between -154 and -72, which contains an AP-1 binding site.Chromatin immunoprecipitation (ChIP) studies indicate that IFNβ increases histone deacetylase (HDAC)-1 recruitment to the MMP-9 promoter and reduces histone H3 acetylation, in addition to reduced NF-κB recruitment.Altogether, our results establish that the repression of MMP-9 transcription in response to IFNβ occurs by the recruitment of HDAC1 via the proximal AP-1 binding site.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, University of South Carolina, Columbia, South Carolina, United States of America.

ABSTRACT
Matrix metalloproteinase-9 (MMP-9) is a 92 kDa zinc-dependant endopeptidase that degrades components of the extracellular matrix. Increased expression of MMP-9 is implicated in many pathological conditions including metastatic cancer, multiple sclerosis, and atherosclerosis. Although it has been widely noted that interferon-β (IFNβ) downregulates both the basal and phorbol 12-myristate 13-acetate (PMA)-induced MMP-9 expression at the transcriptional level, the molecular mechanism of this repression is poorly understood. In the present study we identify a novel mechanism for repression of MMP-9 transcription by IFNβ in HT1080 fibrosarcoma cells. Using reporter assays with promoter deletion constructs we show that IFNβ's inhibitory effects require a region of the promoter between -154 and -72, which contains an AP-1 binding site. Chromatin immunoprecipitation (ChIP) studies indicate that IFNβ increases histone deacetylase (HDAC)-1 recruitment to the MMP-9 promoter and reduces histone H3 acetylation, in addition to reduced NF-κB recruitment. ChIP analysis shows that IFNβ induced HDAC1 recruitment to the MMP-9 promoter and IFNβ mediated transcriptional repression is lost when the AP-1 binding site is inactivated by a point mutation. Altogether, our results establish that the repression of MMP-9 transcription in response to IFNβ occurs by the recruitment of HDAC1 via the proximal AP-1 binding site.

Show MeSH
Related in: MedlinePlus