Abstract
Various cell types in higher multicellular organisms are genetically homogenous, but are functionally and morphologically heterogeneous due to the differential expression of genes during development, which appears to be controlled by epigenetic mechanisms. However, the exact molecular mechanisms that govern the tissue-specific gene expression are poorly understood. Here, we show that dynamic changes in histone modifications and DNA methylation in the upstream coding region of a gene containing the transcription initiation site determine the tissue-specific gene expression pattern. The tissue-specific expression of the transgene correlated with DNA demethylation at specific CpG sites as well as significant changes in histone modifications from a low ratio of methylated H3- lysine 4 or acetylated H3-lysine 9, 14 to acetylated H4 to higher ratios. Based on the programmed status of transgene silenced in cloned mammalian ear-derived fibroblasts, the transgene could be reprogrammed by change of histone modification and DNA methylation by inhibiting both histone deacetylase and DNA methylation, resulting in high expression of the transgene. These findings indicate that dynamic change of histone modification and DNA methylation is potentially important in the establishment and maintenance of tissue-specific gene expression.
Highlights
Various cell types in higher multicellular organisms have in essence an identical genotype
Using the green fluorescence protein (GFP) transgene engineered to be expressed in cloned transgenic pigs, we observed a strong correlation between tissue-specific patterns of gene expression and dynamic changes in histone modification and DNA methylation in the coding region harboring the transcription initiation site
Tissue-specific expression of the transgene coincided with DNA unmethylation at specific CpG sites and a change of histone modification from a low to high ratio of H3-K4 Me/H4-Ac or H3-K9,14 Ac/H4-Ac; it did not correlate with the level of H3-K4 Me
Summary
Various cell types in higher multicellular organisms have in essence an identical genotype. This is due to tissue-specific, temporal and spatial gene expression patterns which are controlled by genetic and epigenetic mechanisms. DNA methylation and histone modifications are two major epigenetic mechanisms that are crucial for tissue- specific gene expression and global gene silencing (Bird, 2002; Li, 2002). Disruption of epigenetic mechanisms which is closely linked to aberrant gene expression leads to abnormal development and, potentially, malignant transformation (Jaenisch and Bird, 2003)
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