In the 1950s and 1960s, Ed Lewis of Caltech discovered the homeodomain encoding genes we now refer to as the Hox genes. One of the most famous mutants that Lewis described is a mutant of the Hox gene Ultrabithorax (Ubx) where the third thoracic (T3) segment of the fly, which normally has a small pair of balancing appendages called halteres, is entirely transformed into a second copy of the second thoracic (T2) segment, with a complete pair of extra wings and second thoracic notum. This incredible homeotic transformation reveals that Ubx is at the top of a regulatory hierarchy that "makes" the third thoracic segment identity and suppresses the development of the second thoracic segment. How can a single transcription factor orchestrate the transformation of an entire segment, with many cell types?
To answer this question, Ryan Loker used whole genome approaches, including ChIP-seq, ATAC-seq, and RNA-seq, to analyze the differences between chromatin structure, gene expression, and transcription factor binding in T2 nuclei and T3 nuclei. Instead of just pooling all nuclei in each segment, Ryan sorted both segments into 'distal' and 'proximal' subsets, allowing him to discover that Ubx changes chromatin structure differently, depending on the proximal-distal position within the segment. One of the surprising findings from Ryan's work is that Ubx appears to be either a transcriptional repressor or transcriptional activator, depending on where in the segment it acts and on the availability of the Hox cofactors Hth and Exd. Moreover, by changing chromatin structure, in particular, chromatin accessibility, Ubx both increases and decreases the ability of other transcription factors to bind their binding sites in T3, compared to the T2 segment.
See Loker et. al, published in Current Biology for the full story.
See also a Q&A published by the Zuckerman Institute's communication team.
The photos of the four winged bithorax fly accompanying this post and the publication were generated by a true master of invertebrate photography, Nicolas Gompel, Professor at the University of Munich.
