Cooption of polyalanine tract into a repressor domain in the mammalian transcription factor HoxA11

Abstract

An enduring problem in biology is explaining how the functions of genes originated and how those functions diverge between species. Despite detailed studies on the functional evolution of a few proteins, the molecular mechanisms by which protein functions have evolved are almost entirely unknown. Here we show that a polyalanine tract in the homeodomain transcription factor HoxA11 arose in the stem-lineage of mammals and functions as an autonomous repressor module by physically interacting with the PAH domains of SIN3 proteins. These results suggest that long polyalanine tracts, which are common in transcription factors and often associated with disease, may generally function as repressor domains and can contribute to the diversification of transcription factor functions despite the deleterious consequences of polyalanine tract expansion.

Terminal regions of a protein are a hotspot for low complexity regions (LCRs) and selection

“…For example, alanine repeats are known to have a role in mediating transcription repression (Janody et al 2001;Maurer et al 2003). The polyalanine domain of transcription factor HoxA11 works as a SIN3A/HDAC1 dependent repressor domain by physically interacting with the PAH domain of the SIN3 protein (Lynch and Wagner 2021). Studies have highlighted that the expansion of polyalanine tracts may contribute to functional diversification in transcription factors (Lynch and Wagner 2021).…”

“…The polyalanine domain of transcription factor HoxA11 works as a SIN3A/HDAC1 dependent repressor domain by physically interacting with the PAH domain of the SIN3 protein (Lynch and Wagner 2021). Studies have highlighted that the expansion of polyalanine tracts may contribute to functional diversification in transcription factors (Lynch and Wagner 2021). Specific pathways prefer certain types of LCRs and amino acids.…”

“…In mammalian proteins, alanine repeat-containing genes are over-represented in DNA-and RNA-binding (Albà and Guigó 2004). Alanine repeats play a prominent role in neurogenesis, signaling, and development (Cocquet et al 2003;Lavoie et al 2003;Caburet et al 2004;Lynch and Wagner 2021). Hence, it is unsurprising to observe a high abundance of alanine repeats across the Tetrapoda clades.…”

Editorial

“…The paper by Crow et al (2020) examines the transcriptional expression patterns of the 5′ HoxA genes in the bluebanded goby. Just as changes in the amino acid sequence of Hox proteins (such as polyalanine expansions in HoxA11 of mammals; Lynch & Wagner, 2021) may lead to novel evolutionary trajectories, tinkering with gene expression and expression domains can also affect changes in morphology of anatomical structures. While genes at the 5′ end of HOX clusters are best known for being associated with axial and limb development in vertebrates, some have been coopted for deployment in other developing structures.…”

“…In the paper by Lynch and Wagner (2021), the effect of a novel polyalanine tract in the HoxA11 homeodomain transcription factor of mammals is assessed with respect to its role in the evolution of the mammalian reproductive and urinary tract. They show that this polyalanine track is restricted to mammals and can exhibit notable repressor effects on other proteins in vitro .…”