The Link Between TGF-β Signaling and Chromatin Dynamics Takes an Unexpected Path

The TGF-β/BMP signaling superfamily plays critical roles in regulating a wide range of physiological and pathological processes. A recent study on Tgfbr1 function during mouse embryonic development found that, in the absence of this gene, the primordium of the external genitalia changes its fate, forming an additional set of hindlimbs and resulting in the so-called "six-legged" mice. Analysis of these embryos demonstrated that Tgfbr1 induces global remodeling of chromatin accessibility, establishing distinct regulatory elements that other morphogenetic factors use to drive either hindlimb or genital development. While global changes in chromatin structure have been previously associated with TGF-β signaling, the alterations seen in six-legged embryos differ significantly from previously described mechanisms. In this review, I discuss these distinctions and underscore the importance of studying biological processes within their natural tissue context, where essential tissue interactions are preserved.