The intimate tango between epigenome and evolution has just taken an interesting spin. With 88% of candidate loci from GWAS (genome wide association studies) pointing toward non-coding regions, the potential for acquired epigenetic marks to explain missing heritability, cross generations, and add variety to populations, offers huge potential for understanding natural variation and evolution, which is only beginning to take effect. Talented scientists at UCSD have revealed a peek at the mechanisms behind the function and evolution of enhancers in order to understand “how regulation is achieved at the nucleotide level in different cell types and environmental contexts.”

Dr. Glass and team at UCSD used “natural genetic variation as an in vivo mutagenesis screen to assess the genome-wide effects of sequence variation.”…in order to investigate …“lineage-determining and signal-specific transcription factor binding, epigenomics and transcriptional outcomes.”

Here’s what they found:

Interrogating enhancer-like regions in the genome, they found genetic evidence that lineage-determining transcription factors (LDTFs) define epigenetic and transcriptomic states.

LDTFs “are dependent on collaborative binding to variably spaced DNA recognition motifs to select enhancers and enable binding of signal-dependent transcription factors”, with“variable motif distances observed”, suggesting “that collaborative binding does not generally require direct protein–protein interactions between the involved transcription factors”

Interestingly, the group observed that “although all cells express hundreds of transcription factors, a large fraction of functional enhancers (~70% in macrophages) are characterized by collaborative interactions involving relatively small sets of lineage-determining transcription factors.”

Overall, these findings provides a solid “explanation for why transcription factor binding is lost at sites where mutations do not occur in the cognate recognition motif.” This was exemplified “in the case of NF-kB”, where “mutations in the motifs for LDTFs were approximately three times more likely to result in decreased binding of NF-kB than mutations in the NF-kB-binding site itself.” The authors conclude that, “This hierarchical model of transcription factor function suggests that limited sets of genomic data for lineage-determining transcription factors and informative histone modifications can be used for the prioritization of disease-associated regulatory variants.”

Get a natural, but enhanced view of epigenetic variation over at Nature, October 2013