What is a Master Regulator?

Copyright: © 2013 Chan SSK, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The term “master regulator” or “master regulatory gene” was first coined by Susumu Ohno over 30 years ago for a “gene that occupies the very top of a regulatory hierarchy,” which, “by its very definition should not be under the regulatory influence of any other gene” [1]. While this term was originally proposed to hypothesize a sex determination mechanism, it was subsequently extended to other disciplines to describe the hierarchy of cell specification in yeasts [2,3], Drosophila [4,5] and plants [6]. Although sex determination could conceivably be imagined to be independent of prior regulatory influences, cell type specification clearly requires some sort of prior regulatory influence, and although “other genes” per se might not have been imagined upstream in the earliest usages of the term, as mechanisms of transcriptional control of development were revealed, this original concept of a gene with nothing upstream was forgotten. However the term “master regulator” stayed attached to these earliest developmental specification factors. The meaning evolved to connote governance over a developmental lineage, but without a proper definition as to what sort of governance specifically was referred to. If any gene that is necessary for the establishment of a given lineage is a master regulator, then the genome might have more masters than servants. On the other hand, if the term master can only be applied when a single unique factor governs a specific lineage, then almost no lineages might qualify to have a master regulator. Use of the term is increasing: Google Scholar identifies 139 publications containing the phrase “master regulator” from 1997 and slightly over 7,000 from 2012. Tracking the presence of the term “master regulator” within all publications that mention the term “regulator” over the past decade and a half demonstrates further how popular the term has become (Figure 1), perhaps to the detriment of scientific clarity. Given that the term is not likely to go away, it would be valuable to agree on parameters of definition that would incorporate the current general sense of meaning, but also provide specificity.