An epigenetic seesaw mechanism works like an analog regulator
https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-017-4353-7
Excerpt from abstract: "
Background
DNA methylation at promoters is largely correlated with inhibition of gene expression. However, the role of DNA methylation at enhancers is not fully understood, although a crosstalk with chromatin marks is expected. Actually, there exist contradictory reports about positive and negative correlations between DNA methylation and H3K4me1, a chromatin hallmark of enhancers.
Results
We investigated the relationship between DNA methylation and active chromatin marks through genome-wide correlations, and found anti-correlation between H3K4me1 and H3K4me3 enrichment at low and intermediate DNA methylation loci. We hypothesized “seesaw” dynamics between H3K4me1 and H3K4me3 in the low and intermediate DNA methylation range, in which DNA methylation discriminates between enhancers and promoters, marked by H3K4me1 and H3K4me3, respectively. Low methylated regions are H3K4me3 enriched, while those with intermediate DNA methylation levels are progressively H3K4me1 enriched. Additionally, the enrichment of H3K27ac, distinguishing active from primed enhancers, follows a plateau in the lower range of the intermediate DNA methylation level, corresponding to active enhancers, and decreases linearly in the higher range of the intermediate DNA methylation. Thus, the decrease of the DNA methylation switches smoothly the state of the enhancers from a primed to an active state. We summarize these observations into a rule of thumb of one-out-of-three methylation marks: “In each genomic region only one out of these three methylation marks {DNA methylation, H3K4me1, H3K4me3} is high. If it is the DNA methylation, the region is inactive. If it is H3K4me1, the region is an enhancer, and if it is H3K4me3, the region is a promoter”. To test our model, we used available genome-wide datasets of H3K4 methyltransferases knockouts. Our analysis suggests that CXXC proteins, as readers of non-methylated CpGs would regulate the “seesaw” mechanism that focuses H3K4me3 to unmethylated sites, while being repulsed from H3K4me1 decorated enhancers and CpG island shores.
Background
DNA methylation at promoters is largely correlated with inhibition of gene expression. However, the role of DNA methylation at enhancers is not fully understood, although a crosstalk with chromatin marks is expected. Actually, there exist contradictory reports about positive and negative correlations between DNA methylation and H3K4me1, a chromatin hallmark of enhancers.
Results
We investigated the relationship between DNA methylation and active chromatin marks through genome-wide correlations, and found anti-correlation between H3K4me1 and H3K4me3 enrichment at low and intermediate DNA methylation loci. We hypothesized “seesaw” dynamics between H3K4me1 and H3K4me3 in the low and intermediate DNA methylation range, in which DNA methylation discriminates between enhancers and promoters, marked by H3K4me1 and H3K4me3, respectively. Low methylated regions are H3K4me3 enriched, while those with intermediate DNA methylation levels are progressively H3K4me1 enriched. Additionally, the enrichment of H3K27ac, distinguishing active from primed enhancers, follows a plateau in the lower range of the intermediate DNA methylation level, corresponding to active enhancers, and decreases linearly in the higher range of the intermediate DNA methylation. Thus, the decrease of the DNA methylation switches smoothly the state of the enhancers from a primed to an active state. We summarize these observations into a rule of thumb of one-out-of-three methylation marks: “In each genomic region only one out of these three methylation marks {DNA methylation, H3K4me1, H3K4me3} is high. If it is the DNA methylation, the region is inactive. If it is H3K4me1, the region is an enhancer, and if it is H3K4me3, the region is a promoter”. To test our model, we used available genome-wide datasets of H3K4 methyltransferases knockouts. Our analysis suggests that CXXC proteins, as readers of non-methylated CpGs would regulate the “seesaw” mechanism that focuses H3K4me3 to unmethylated sites, while being repulsed from H3K4me1 decorated enhancers and CpG island shores.
Conclusions
Our results show that DNA methylation discriminates promoters from enhancers through H3K4me1-H3K4me3 seesaw mechanism, and suggest its possible function in the inheritance of chromatin marks after cell division. Our analyses suggest aberrant formation of promoter-like regions and ectopic transcription of hypomethylated regions of DNA. Such mechanism process can have important implications in biological process in where it has been reported abnormal DNA methylation status such as cancer and aging.
Discussion
...different cells of a population can have different chromatin marks at the same genomic region, and such marks are dynamically changed through the enzymatic activity of methylases and demethylases. Therefore, we use the term “seesaw” rather than “mutual exclusion” to define such mechanism, which includes a balanced state with both marks enriched at lower levels."
My comment: DNA methylation regulates discrimination of enhancers from promoters through two different histone marker sets. Enhancers and promoters are widely used by the cell in a mechanism called alternative splicing, which makes it possible for the cell to produce thousands of different proteins based just on one multifunctional gene. DNA methylation patterns are typically affected by diet type, climate, stress etc. which means that these clever mechanisms help organisms go through their ecological adaptation processes. The seesaw mechanism provides a balanced state between two analog type regulatory functions. The interaction between several genomic elements points to Design and Creation. There are no mechanisms for evolution because any change in organisms is based on epigenetic regulation of existing biological information OR loss of it. Don't get lost.
...different cells of a population can have different chromatin marks at the same genomic region, and such marks are dynamically changed through the enzymatic activity of methylases and demethylases. Therefore, we use the term “seesaw” rather than “mutual exclusion” to define such mechanism, which includes a balanced state with both marks enriched at lower levels."
My comment: DNA methylation regulates discrimination of enhancers from promoters through two different histone marker sets. Enhancers and promoters are widely used by the cell in a mechanism called alternative splicing, which makes it possible for the cell to produce thousands of different proteins based just on one multifunctional gene. DNA methylation patterns are typically affected by diet type, climate, stress etc. which means that these clever mechanisms help organisms go through their ecological adaptation processes. The seesaw mechanism provides a balanced state between two analog type regulatory functions. The interaction between several genomic elements points to Design and Creation. There are no mechanisms for evolution because any change in organisms is based on epigenetic regulation of existing biological information OR loss of it. Don't get lost.
