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Histone deacetylase inhibition downregulates collagen 3A1 in fibrotic lung fibroblasts.

Zhang X, Liu H, Hock T, Thannickal VJ, Sanders YY - Int J Mol Sci (2013)

Bottom Line: The deacetylation inhibitor effect of SAHA was verified by observing higher acetylation levels of both histone H3 and H4 in treated IPF cells.Chromatin immunoprecipitation (ChIP) experiments demonstrated that the reduced expression of COL3A1 by SAHA is with increased association of the repressive chromatin marker, H3K27Me3, and decreased association of the active chromatin marker, H3K9Ac.Our data indicate that the HDACi SAHA alters the chromatin associated with COL3A1, resulting in its decreased expression.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. yans@uab.edu.

ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a deadly disease characterized by chronic inflammation and excessive collagen accumulation in the lung. Myofibroblasts are the primary collagen-producing cells in pulmonary fibrosis. Histone deacetylase inhibitor (HDACi) can affect gene expression, and some, such as suberoylanilide hydroxamic acid (SAHA), are US FDA approved for cancer treatment. In this study, we investigated SAHA's effects on the expression of collagen III alpha 1 (COL3A1) in primary human IPF fibroblasts and in a murine model of pulmonary fibrosis. We observed that increased COL3A1 expression in IPF fibroblasts can be substantially reduced by SAHA treatment at the level of transcription as detected by RT-PCR; collagen III protein level was also reduced, as detected by Western blots and immunofluorescence. The deacetylation inhibitor effect of SAHA was verified by observing higher acetylation levels of both histone H3 and H4 in treated IPF cells. Chromatin immunoprecipitation (ChIP) experiments demonstrated that the reduced expression of COL3A1 by SAHA is with increased association of the repressive chromatin marker, H3K27Me3, and decreased association of the active chromatin marker, H3K9Ac. In our murine model of bleomycin-induced pulmonary fibrosis, the SAHA treated group demonstrated significantly less collagen III, as detected by immunohistochemistry. Our data indicate that the HDACi SAHA alters the chromatin associated with COL3A1, resulting in its decreased expression.

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Idiopathic pulmonary fibrosis (IPF) lung tissues (A) and primary fibroblasts (B) have higher COL3A1 mRNA expression when compared to control samples by real-time RT-PCR. Results are the average of at least three independent experiments (IPF or Control lung tissue samples, n = 3). Bars indicate the mean ± SD. * p < 0.05 compared to the non-IPF control.
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f1-ijms-14-19605: Idiopathic pulmonary fibrosis (IPF) lung tissues (A) and primary fibroblasts (B) have higher COL3A1 mRNA expression when compared to control samples by real-time RT-PCR. Results are the average of at least three independent experiments (IPF or Control lung tissue samples, n = 3). Bars indicate the mean ± SD. * p < 0.05 compared to the non-IPF control.

Mentions: We first compared the COL3A1 mRNA expression in IPF and normal control lung tissues. Using real-time RT-PCR, significantly increased COL3A1 expression was detected in IPF lung tissues compared to control samples (Figure 1A). In cultured primary IPF, fibroblasts displayed moderately, but statistically higher COL3A1 expression (Figure 1B) compared to the control cells. These data are consistent with previously published microarray data [12,14].


Histone deacetylase inhibition downregulates collagen 3A1 in fibrotic lung fibroblasts.

Zhang X, Liu H, Hock T, Thannickal VJ, Sanders YY - Int J Mol Sci (2013)

Idiopathic pulmonary fibrosis (IPF) lung tissues (A) and primary fibroblasts (B) have higher COL3A1 mRNA expression when compared to control samples by real-time RT-PCR. Results are the average of at least three independent experiments (IPF or Control lung tissue samples, n = 3). Bars indicate the mean ± SD. * p < 0.05 compared to the non-IPF control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3821575&req=5

f1-ijms-14-19605: Idiopathic pulmonary fibrosis (IPF) lung tissues (A) and primary fibroblasts (B) have higher COL3A1 mRNA expression when compared to control samples by real-time RT-PCR. Results are the average of at least three independent experiments (IPF or Control lung tissue samples, n = 3). Bars indicate the mean ± SD. * p < 0.05 compared to the non-IPF control.
Mentions: We first compared the COL3A1 mRNA expression in IPF and normal control lung tissues. Using real-time RT-PCR, significantly increased COL3A1 expression was detected in IPF lung tissues compared to control samples (Figure 1A). In cultured primary IPF, fibroblasts displayed moderately, but statistically higher COL3A1 expression (Figure 1B) compared to the control cells. These data are consistent with previously published microarray data [12,14].

Bottom Line: The deacetylation inhibitor effect of SAHA was verified by observing higher acetylation levels of both histone H3 and H4 in treated IPF cells.Chromatin immunoprecipitation (ChIP) experiments demonstrated that the reduced expression of COL3A1 by SAHA is with increased association of the repressive chromatin marker, H3K27Me3, and decreased association of the active chromatin marker, H3K9Ac.Our data indicate that the HDACi SAHA alters the chromatin associated with COL3A1, resulting in its decreased expression.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. yans@uab.edu.

ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a deadly disease characterized by chronic inflammation and excessive collagen accumulation in the lung. Myofibroblasts are the primary collagen-producing cells in pulmonary fibrosis. Histone deacetylase inhibitor (HDACi) can affect gene expression, and some, such as suberoylanilide hydroxamic acid (SAHA), are US FDA approved for cancer treatment. In this study, we investigated SAHA's effects on the expression of collagen III alpha 1 (COL3A1) in primary human IPF fibroblasts and in a murine model of pulmonary fibrosis. We observed that increased COL3A1 expression in IPF fibroblasts can be substantially reduced by SAHA treatment at the level of transcription as detected by RT-PCR; collagen III protein level was also reduced, as detected by Western blots and immunofluorescence. The deacetylation inhibitor effect of SAHA was verified by observing higher acetylation levels of both histone H3 and H4 in treated IPF cells. Chromatin immunoprecipitation (ChIP) experiments demonstrated that the reduced expression of COL3A1 by SAHA is with increased association of the repressive chromatin marker, H3K27Me3, and decreased association of the active chromatin marker, H3K9Ac. In our murine model of bleomycin-induced pulmonary fibrosis, the SAHA treated group demonstrated significantly less collagen III, as detected by immunohistochemistry. Our data indicate that the HDACi SAHA alters the chromatin associated with COL3A1, resulting in its decreased expression.

Show MeSH
Related in: MedlinePlus