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1.  Epigenetics as an answer to Darwin’s “special difficulty” 
Frontiers in Genetics  2014;5:321.
Epigenetic modifications produce distinct phenotypes from the same genome through genome-wide transcriptional control. Recently, DNA methylation in honeybees and histone modifications in ants were found to assist the formation of caste phenotypes during development and adulthood. This insight allows us to revisit one of Darwin’s greatest challenges to his natural selection theory; the derivation of multiple forms of sterile workers within eusocial species. Differential feeding of larvae creates two distinct developmental paths between queens and workers, with workers further refined by pheromone cues. Flexible epigenetic control provides a mechanism to interpret the milieu of social cues that create distinct worker sub-caste phenotypes. Recent findings suggest a distinct use for DNA methylation before and after adult emergence. Further, a comparison of genes that are differentially methylated and transcriptionally altered upon pheromone signaling suggests that epigenetics can play a key role in mediating pheromone signals to derive sub-caste phenotypes. Epigenetic modifications may provide a molecular mechanism to Darwin’s ”special difficulty” and explain the emergence of multiple sub-phenotypes among sterile individuals.
PMCID: PMC4162389  PMID: 25309578
epigenetics; evolution; genomics; developmental plasticity; eusociality; behavior; pheromones
2.  Reversible switching between epigenetic states in honeybee behavioral subcastes 
Nature neuroscience  2012;15(10):1371-1373.
In honeybee societies, distinct caste phenotypes are created from the same genotype, suggesting a role for epigenetics in deriving these behaviorally different phenotypes. We found no differences in DNA methylation between irreversible worker/queen castes, but substantial differences between nurses and forager subcastes. Reverting foragers back to nurses reestablished methylation levels for a majority of genes and provided the first evidence in any organism of reversible epigenetic changes associated with behavior.
PMCID: PMC3518384  PMID: 22983211
3.  Adaptation of the CHARM DNA methylation platform for the rat genome reveals novel brain region-specific differences 
Epigenetics  2011;6(11):1378-1390.
Comprehensive high-throughput arrays for relative methylation (CHARM) was recently developed as an experimental platform and analytic approach to assess DNA methylation (DNAm) at a genome-wide level. Its initial implementation was for human and mouse. We adapted it for rat and sought to examine DNAm differences across tissues and brain regions in this model organism. We extracted DNA from liver, spleen and three brain regions: cortex, hippocampus and hypothalamus from adult Sprague Dawley rats. DNA was digested with McrBC, and the resulting methyl-depleted fraction was hybridized to the rat CHARM array along with a mock-treated fraction. Differentially methylated regions (DMRs) between tissue types were detected using normalized methylation log-ratios. In validating 24 of the most significant DMRs by bisulfite pyrosequencing, we detected large mean differences in DNAm, ranging from 33–59%, among the most significant DMRs in the across-tissue comparisons. The comparable figures for the hippocampus vs. hypothalamus DMRs were 14–40%, for the cortex vs. hippocampus DMRs, 12–29%, and for the cortex vs. hypothalamus DMRs, 5–35%, with a correlation of r2 = 0.92 between the methylation differences in 24 DMRs predicted by CHARM and those validated by bisulfite pyrosequencing. Our adaptation of the CHARM array for the rat genome yielded highly robust results that demonstrate the value of this method in detecting substantial DNAm differences between tissues and across different brain regions. This platform should prove valuable in future studies aimed at examining DNAm differences in particular brain regions of rats exposed to environmental stimuli with potential epigenetic consequences.
PMCID: PMC3242812  PMID: 22048247
epigenetics; DNA methylation; methylation array; genome-wide; rat; brain
4.  Accurate genome-scale percentage DNA methylation estimates from microarray data 
Biostatistics (Oxford, England)  2010;12(2):197-210.
DNA methylation is a key regulator of gene function in a multitude of both normal and abnormal biological processes, but tools to elucidate its roles on a genome-wide scale are still in their infancy. Methylation sensitive restriction enzymes and microarrays provide a potential high-throughput, low-cost platform to allow methylation profiling. However, accurate absolute methylation estimates have been elusive due to systematic errors and unwanted variability. Previous microarray preprocessing procedures, mostly developed for expression arrays, fail to adequately normalize methylation-related data since they rely on key assumptions that are violated in the case of DNA methylation. We develop a normalization strategy tailored to DNA methylation data and an empirical Bayes percentage methylation estimator that together yield accurate absolute methylation estimates that can be compared across samples. We illustrate the method on data generated to detect methylation differences between tissues and between normal and tumor colon samples.
PMCID: PMC3062148  PMID: 20858772
DNA methylation; Epigenetics; Microarray
5.  Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts 
Nature genetics  2009;41(12):1350-1353.
Induced pluripotent stem (iPS) cells are derived by epigenetic reprogramming, but their DNA methylation patterns have not yet been analyzed on a genome-wide scale. Here, we find substantial hypermethylation and hypomethylation of cytosine-phosphate-guanine (CpG) island shores in nine human iPS cell lines as compared to their parental fibroblasts. The differentially methylated regions (DMRs) in the reprogrammed cells (denoted R-DMRs) were significantly enriched in tissue-specific (T-DMRs; 2.6-fold, P < 10−4) and cancer-specific DMRs (C-DMRs; 3.6-fold, P < 10−4). Notably, even though the iPS cells are derived from fibroblasts, their R-DMRs can distinguish between normal brain, liver and spleen cells and between colon cancer and normal colon cells. Thus, many DMRs are broadly involved in tissue differentiation, epigenetic reprogramming and cancer. We observed colocalization of hypomethylated R-DMRs with hypermethylated C-DMRs and bivalent chromatin marks, and colocalization of hypermethylated R-DMRs with hypomethylated C-DMRs and the absence of bivalent marks, suggesting two mechanisms for epigenetic reprogramming in iPS cells and cancer.
PMCID: PMC2958040  PMID: 19881528

Results 1-5 (5)