On 2013 Oct 23, Albert Erives commented:

The background motivation of this paper is well written and informative. The "fine structure" of transcriptional enhancers underlying animal development is worthy of study and it is refreshing to see affirmation that there may be a range of simple to structured regulatory DNAs. From this report on Svb target enhancers, it will be important to follow-up on whether there are functional consequences to the range of architectures.

Also of interest is the following. The authors note that: "[t]hese findings highlight a paradoxical discrepancy between the enrichment of putative BSs accumulated in Svb downstream genes and the limited number of those acting as cis-regulatory elements. Is there a role for this evolutionary accumulation of Svb-like motifs in Svb targets?" This is an important question that is related to the broader issues of homotypic site clustering and related phenomenon mentioned in this paper's background. Though my lab's work is nicely integrated into the introduction, there is one additional key study of ours that is most relevant to these issues: "Dynamic evolution of precise regulatory encodings creates the clustered site signature of enhancers" (Crocker J, 2010). I suspect this one issue, and a difficulty in experimentally testing the function of every single sequence component of a homotypic site cluster, has facilitated the generally-assumed working model that each sequence component in a cluster or locus remains functional in the extant organisms from they have been isolated (I take issues with this model on several grounds). To some extent this is a question that preceded the more recent debate about "biochemical functionality" in the ENCODE data sets. This report is another step towards a more versatile, effective, and evolutionarily-grounded language of enhancer biology.

On 2013 Oct 23, Albert Erives commented:

The background motivation of this paper is well written and informative. The "fine structure" of transcriptional enhancers underlying animal development is worthy of study and it is refreshing to see affirmation that there may be a range of simple to structured regulatory DNAs. From this report on Svb target enhancers, it will be important to follow-up on whether there are functional consequences to the range of architectures.

Also of interest is the following. The authors note that: "[t]hese findings highlight a paradoxical discrepancy between the enrichment of putative BSs accumulated in Svb downstream genes and the limited number of those acting as cis-regulatory elements. Is there a role for this evolutionary accumulation of Svb-like motifs in Svb targets?" This is an important question that is related to the broader issues of homotypic site clustering and related phenomenon mentioned in this paper's background. Though my lab's work is nicely integrated into the introduction, there is one additional key study of ours that is most relevant to these issues: "Dynamic evolution of precise regulatory encodings creates the clustered site signature of enhancers" (Crocker J, 2010). I suspect this one issue, and a difficulty in experimentally testing the function of every single sequence component of a homotypic site cluster, has facilitated the generally-assumed working model that each sequence component in a cluster or locus remains functional in the extant organisms from they have been isolated (I take issues with this model on several grounds). To some extent this is a question that preceded the more recent debate about "biochemical functionality" in the ENCODE data sets. This report is another step towards a more versatile, effective, and evolutionarily-grounded language of enhancer biology.