Fig. 7: The hierarchical model and the three-part code principle underlying EE subtype diversity.

a Pros is a selector protein in defining EE identity, as it serves at the top of the hierarchy and globally regulates the transcription of both the second level (2⁰) TFs [including but not limited to Ptx1 and Mirr (whose expression also requires Notch activity)], and the third level (3⁰) TFs, the expression of many of which also requires local or regional factors. b The combination principles of the three-part TF code and the theoretical combination possibilities underlying EE diversity. There is only one 1⁰ TF (Pros); the 2⁰ TFs include Ptx1 and Mirr, and potentially additional ones, such as the ones for class III EE identity; and there are multiple (>12) 3⁰ TFs. c The TF code model in determining class EE subtypes and sub-class EE subtypes. The combination of Pros and one of the 2⁰ TFs determines the identity of the major subtypes (such as class I and II); and the combination of Pros, 2⁰ TF, and 3⁰ TFs further refines enhancer activity and determines subclass EE subtypes and hormone expression profiles. Conceivably, further addition of co-activators or co-repressors may allow additional diversity of EE subtypes, and/or generation of dynamic hormone expression patterns for each specific EE subtypes.