Of Mice and Men: The Evolution of Cis-Regulatory Elements
DNase Hypersenestive sites (DHSs) are regions within the genome that are susceptible to cleavage by the enzyme DNase I. These regions are susceptible because they lie in uncondensed regions of euchromatin and are readily accessible to the DNase enzyme. In vivo however, these regions are also accessible to regulatory proteins as well as other molecular machinery and thus are functionally associated with active transcription. DHS patterns serve as an internal code for a cell’s fate and identity, and inform an organisms’ development trajectory. The mapping of DHSs serves as a method for identifying cis-regulatory elements (regions of non-coding DNA that regulate expression of local genes) throughout the genome. A recent study published in Science by Vierstra et al. constructed DHS maps of 45 mouse cell and tissue types and compared them to their corresponding tissues in humans in efforts to investigate the evolutionary dynamics of regulatory DNA.
In the mouse genome, they identified between 74,000 and 219,000 DHSs per cell, for a total of 1.3 million combined. They next compared these regions to the human genome. 35.6% of the DHSs identified in the mouse genome were found to be highly conserved in humans and shared a high sequence homology. 23.9% were not found in the human genome, but an astonishing 41.5% of the DHSs found in mouse were found in the same cells and in the same locations as humans – but did not share any sequence homology! The authors suggest that this evidence indicates that while there has been evolutionary pressure to keep these sites accessible, the exact sequences have not been too important across evolution!
The group also found that upwards of 69% of the shared DHSs have been “repurposed” within the two organisms, depending on the tissue context. The authors argue that this repurposing from one tissue context to another is an important mechanism by which the cis-regulatory landscape evolves. They also found that transcription factor (TF) recognition sites were conserved within DHSs that were conserved in orthologous tissues. In contrast, TF recognition sites were preferentially lost in DHSs that had been repurposed due to a loss of selective pressure. The loss of TF recognition sites most likely occurred over evolutionary time through small random mutations. While the buildup of these mutations would ultimately result in the loss of TF function, it also made way for the formation of novel TF recognition sites.
Mouse and human cis-regulatory elements have undergone extensive rewiring and DHSs have been lost, gained, and repurposed. The authors conclude that the plasticity seen in cis-regulatory elements allows for the development of novel functions within the genome and thus is an important mechanism of evolution!
Vierstra J, Rynes E, Sandstrom R, Zhang M, Canfield T, Hansen RS, Stehling-Sun S, Sabo PJ, Byron R, Humbert R, Thurman RE, Johnson AK, Vong S, Lee K, Bates D, Neri F, Diegel M, Giste E, Haugen E, Dunn D, Wilken MS, Josefowicz S, Samstein R, Chang KH, Eichler EE, De Bruijn M, Reh TA, Skoultchi A, Rudensky A, Orkin SH, Papayannopoulou T, Treuting PM, Selleri L, Kaul R, Groudine M, Bender MA, & Stamatoyannopoulos JA (2014). Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution. Science (New York, N.Y.), 346 (6212), 1007-12 PMID: 25411453