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Sexually Dimorphic Expression of eGFP Transgene in the Akr1A1 Locus of Mouse Liver Regulated by Sex Hormone-Related Epigenetic Remodeling.

Lai CW, Chen HL, Tsai TC, Chu TW, Yang SH, Chong KY, Chen CM - Sci Rep (2016)

Bottom Line: However, the mechanism of sexually dimorphic expression is still not fully understood.In this study, a pCAG-eGFP transgenic mouse strain with a specific transgene integration site in the Akr1A1 locus presented male-biased EGFP expression in the liver, and the expression was activated by testosterone during puberty.The integration of the pCAG-eGFP transgene altered the epigenetic regulation of the adjacent chromatin, including increased binding of STAT5b, a sexually dimorphic expression regulator, and the transformation of DNA methylation from hypermethylation into male-biased hypomethylation.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences, and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.

ABSTRACT
Sexually dimorphic gene expression is commonly found in the liver, and many of these genes are linked to different incidences of liver diseases between sexes. However, the mechanism of sexually dimorphic expression is still not fully understood. In this study, a pCAG-eGFP transgenic mouse strain with a specific transgene integration site in the Akr1A1 locus presented male-biased EGFP expression in the liver, and the expression was activated by testosterone during puberty. The integration of the pCAG-eGFP transgene altered the epigenetic regulation of the adjacent chromatin, including increased binding of STAT5b, a sexually dimorphic expression regulator, and the transformation of DNA methylation from hypermethylation into male-biased hypomethylation. Through this de novo sexually dimorphic expression of the transgene, the Akr1A1(eGFP) mouse provides a useful model to study the mechanisms and the dynamic changes of sexually dimorphic gene expression during either development or pathogenesis of the liver.

No MeSH data available.


Related in: MedlinePlus

The EGFP expression changes between the livers of the male and female Akr1A1eGFP/+ mice during MCD diet-induced NAFLD.(A) The device for EGFP live fluorescence imaging of the Tg mouse liver. (B) The body weight change of the Tg mice during MCD diet-induced NAFLD. (C) The EGFP live fluorescence imaging of the Tg mouse livers on the 1st and 28th days of MCD diet-induced NAFLD. (D) The EGFP expression and morphology of the Tg mouse liver from mice fed a regular or an MCD diet for 4 weeks. The in vivo EGFP fluorescence imaging (a, b, g, h); the EGFP fluorescence in the frozen sections (c, d, i, j); H & E staining (e, f, k, l); Scale bar: 50 μm; CV: central vein; the black and white arrowheads represent the location of the central vein and the portal vein, respectively; the body weight is shown as the mean ± s.e.m. of five animals per group (n = 5).
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f8: The EGFP expression changes between the livers of the male and female Akr1A1eGFP/+ mice during MCD diet-induced NAFLD.(A) The device for EGFP live fluorescence imaging of the Tg mouse liver. (B) The body weight change of the Tg mice during MCD diet-induced NAFLD. (C) The EGFP live fluorescence imaging of the Tg mouse livers on the 1st and 28th days of MCD diet-induced NAFLD. (D) The EGFP expression and morphology of the Tg mouse liver from mice fed a regular or an MCD diet for 4 weeks. The in vivo EGFP fluorescence imaging (a, b, g, h); the EGFP fluorescence in the frozen sections (c, d, i, j); H & E staining (e, f, k, l); Scale bar: 50 μm; CV: central vein; the black and white arrowheads represent the location of the central vein and the portal vein, respectively; the body weight is shown as the mean ± s.e.m. of five animals per group (n = 5).

Mentions: The sexually dimorphic EGFP-expressing Tg mice in this study may provide a useful model to study the expression changes of endogenous sexually dimorphic genes. An MCD dietary model, which impairs the VLDL secretion pathway and results in lipid accumulation in the liver, is the most commonly used model to induce NAFLD in rodents. To demonstrate the differential expression changes of the sexually dimorphic EGFP in the livers of male and female mice during NAFLD pathogenesis, the Akr1A1eGFP/+ mice were fed an MCD diet for 4 weeks, and EGFP expression was monitored at day 0 and day 28 by live fluorescence imaging in the same mouse liver (Fig. 8A). The results showed that both the male and female mice lost approximately 35% of their body weight (Fig. 8B) and presented extensive microvesicular steatosis around the central vein of the hepatic lobule after 4 weeks on the MCD diet (Fig. 8D(i–l)), which are significant features of MCD diet-induced NAFLD. EGFP expression was increased in the livers of females at day 28 compared with day 0 in the same mouse, and no obvious changes were observed in the livers of males (Fig. 8C). The results of the in vivo EGFP fluorescence imaging showed that the sexual dimorphism of EGFP expression between MCD-fed male and female mice was reduced compared to the Tg mice that were fed a regular diet, and EGFP distribution in the MCD-fed female mice was extended to the hepatic lobules rather than limited to the central vein of the livers as in the regular diet group (Fig. 8D). Accordingly, the change in the sexually dimorphic EGFP fluorescence in the Tg mice livers was followed by pathogenesis of the MCD diet-induced NAFLD, and thus, the in vivo EGFP imaging may be useful as a marker for endogenous sexually dimorphic gene expression in the liver.


Sexually Dimorphic Expression of eGFP Transgene in the Akr1A1 Locus of Mouse Liver Regulated by Sex Hormone-Related Epigenetic Remodeling.

Lai CW, Chen HL, Tsai TC, Chu TW, Yang SH, Chong KY, Chen CM - Sci Rep (2016)

The EGFP expression changes between the livers of the male and female Akr1A1eGFP/+ mice during MCD diet-induced NAFLD.(A) The device for EGFP live fluorescence imaging of the Tg mouse liver. (B) The body weight change of the Tg mice during MCD diet-induced NAFLD. (C) The EGFP live fluorescence imaging of the Tg mouse livers on the 1st and 28th days of MCD diet-induced NAFLD. (D) The EGFP expression and morphology of the Tg mouse liver from mice fed a regular or an MCD diet for 4 weeks. The in vivo EGFP fluorescence imaging (a, b, g, h); the EGFP fluorescence in the frozen sections (c, d, i, j); H & E staining (e, f, k, l); Scale bar: 50 μm; CV: central vein; the black and white arrowheads represent the location of the central vein and the portal vein, respectively; the body weight is shown as the mean ± s.e.m. of five animals per group (n = 5).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4834580&req=5

f8: The EGFP expression changes between the livers of the male and female Akr1A1eGFP/+ mice during MCD diet-induced NAFLD.(A) The device for EGFP live fluorescence imaging of the Tg mouse liver. (B) The body weight change of the Tg mice during MCD diet-induced NAFLD. (C) The EGFP live fluorescence imaging of the Tg mouse livers on the 1st and 28th days of MCD diet-induced NAFLD. (D) The EGFP expression and morphology of the Tg mouse liver from mice fed a regular or an MCD diet for 4 weeks. The in vivo EGFP fluorescence imaging (a, b, g, h); the EGFP fluorescence in the frozen sections (c, d, i, j); H & E staining (e, f, k, l); Scale bar: 50 μm; CV: central vein; the black and white arrowheads represent the location of the central vein and the portal vein, respectively; the body weight is shown as the mean ± s.e.m. of five animals per group (n = 5).
Mentions: The sexually dimorphic EGFP-expressing Tg mice in this study may provide a useful model to study the expression changes of endogenous sexually dimorphic genes. An MCD dietary model, which impairs the VLDL secretion pathway and results in lipid accumulation in the liver, is the most commonly used model to induce NAFLD in rodents. To demonstrate the differential expression changes of the sexually dimorphic EGFP in the livers of male and female mice during NAFLD pathogenesis, the Akr1A1eGFP/+ mice were fed an MCD diet for 4 weeks, and EGFP expression was monitored at day 0 and day 28 by live fluorescence imaging in the same mouse liver (Fig. 8A). The results showed that both the male and female mice lost approximately 35% of their body weight (Fig. 8B) and presented extensive microvesicular steatosis around the central vein of the hepatic lobule after 4 weeks on the MCD diet (Fig. 8D(i–l)), which are significant features of MCD diet-induced NAFLD. EGFP expression was increased in the livers of females at day 28 compared with day 0 in the same mouse, and no obvious changes were observed in the livers of males (Fig. 8C). The results of the in vivo EGFP fluorescence imaging showed that the sexual dimorphism of EGFP expression between MCD-fed male and female mice was reduced compared to the Tg mice that were fed a regular diet, and EGFP distribution in the MCD-fed female mice was extended to the hepatic lobules rather than limited to the central vein of the livers as in the regular diet group (Fig. 8D). Accordingly, the change in the sexually dimorphic EGFP fluorescence in the Tg mice livers was followed by pathogenesis of the MCD diet-induced NAFLD, and thus, the in vivo EGFP imaging may be useful as a marker for endogenous sexually dimorphic gene expression in the liver.

Bottom Line: However, the mechanism of sexually dimorphic expression is still not fully understood.In this study, a pCAG-eGFP transgenic mouse strain with a specific transgene integration site in the Akr1A1 locus presented male-biased EGFP expression in the liver, and the expression was activated by testosterone during puberty.The integration of the pCAG-eGFP transgene altered the epigenetic regulation of the adjacent chromatin, including increased binding of STAT5b, a sexually dimorphic expression regulator, and the transformation of DNA methylation from hypermethylation into male-biased hypomethylation.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences, and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.

ABSTRACT
Sexually dimorphic gene expression is commonly found in the liver, and many of these genes are linked to different incidences of liver diseases between sexes. However, the mechanism of sexually dimorphic expression is still not fully understood. In this study, a pCAG-eGFP transgenic mouse strain with a specific transgene integration site in the Akr1A1 locus presented male-biased EGFP expression in the liver, and the expression was activated by testosterone during puberty. The integration of the pCAG-eGFP transgene altered the epigenetic regulation of the adjacent chromatin, including increased binding of STAT5b, a sexually dimorphic expression regulator, and the transformation of DNA methylation from hypermethylation into male-biased hypomethylation. Through this de novo sexually dimorphic expression of the transgene, the Akr1A1(eGFP) mouse provides a useful model to study the mechanisms and the dynamic changes of sexually dimorphic gene expression during either development or pathogenesis of the liver.

No MeSH data available.


Related in: MedlinePlus