Many chose to focus on the ‘wealthy’ two percent of our genome that produces protein, but we’ve always found the other 98% to be much more interesting. Thankfully, we’re past the days of referring to non-coding, intergenic regions as ‘Junk DNA’, and new research is proving how scientifically rich they really are.

Dr. Emily Hodges and her comrades at Cold Spring Harbor Laboratory carried out “deep sequencing of mammalian DNA methylomes” and “uncovered a previously unpredicted number of discrete hypomethylated regions in intergenic space (iHMRs).” They accomplished this by “comparing HMR profiles in embryonic stem and primary blood cells” while using “combined whole-genome bisulfite sequencing data with extensive gene expression and chromatin-state data.” The end goal was to define “functional classes of iHMRs”, while also reconstructing “the dynamics of their establishment in a developmental setting”, and here are the results:

“iHMRs mark an exclusive subset of active DNase hypersensitive sites (DHS)” and represent a perfect landing site for transcriptional machinery as indeed “both developmentally constitutive and cell-type-specific iHMRs display chromatin states typical of distinct regulatory elements. “

“iHMR changes are more predictive of nearby gene activity than the promoter HMR itself, and that expression of noncoding RNAs within the iHMR accompanies full activation and complete demethylation of mature (B cell) enhancers.”

“Conserved sequence features corresponding to iHMR transcript start sites, including a discernible TATA motif, suggest a conserved, functional role for transcription in these regions.”

But the bold navigators of the intergenome weren’t done there. They then went on and “explored both primate-specific and human population variation at iHMRs, finding that while enhancer iHMRs are more variable in sequence and methylation status than any other functional class…”, meaning that the “…conservation of the TATA box is highly predictive of iHMR maintenance…”. Ultimately, this reflects “the impact of sequence plasticity and transcriptional signals on iHMR establishment.”

When it comes down to the big picture, their analysis allowed them to construct a three-step timeline in which:

Intergenic DHS are pre-established in the stem cell Partial demethylation of intergenic DHSs occurs Complete iHMR formation and transcription coincide with enhancer activation

Read in-between the genomic lines over at Genome Research, October 2013.