Variation in Homeodomain DNA Binding Revealed by High-Resolution Analysis of Sequence Preferences

Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Cell (Impact Factor: 33.12). 07/2008; 133(7):1266-76. DOI: 10.1016/j.cell.2008.05.024
Source: PubMed

ABSTRACT Most homeodomains are unique within a genome, yet many are highly conserved across vast evolutionary distances, implying strong selection on their precise DNA-binding specificities. We determined the binding preferences of the majority (168) of mouse homeodomains to all possible 8-base sequences, revealing rich and complex patterns of sequence specificity and showing that there are at least 65 distinct homeodomain DNA-binding activities. We developed a computational system that successfully predicts binding sites for homeodomain proteins as distant from mouse as Drosophila and C. elegans, and we infer full 8-mer binding profiles for the majority of known animal homeodomains. Our results provide an unprecedented level of resolution in the analysis of this simple domain structure and suggest that variation in sequence recognition may be a factor in its functional diversity and evolutionary success.

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Available from: Olga Borisovna Botvinnik, Jul 28, 2015
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    • "The inference scheme described here relies on the high degree of conservation among DBDs. Indeed, our analyses confirm the ''deep homology'' that has been described for metazoan developmental processes and the TFs that regulate them (e.g., homeodomains) (Berger et al., 2008; Carroll, 2008; Noyes et al., 2008) and furthermore indicate that deep homology is a property of the sequence preferences of many TFs in all eukaryotic kingdoms. Our initial analyses (data not shown) suggest that many motifs likely date to the base of metazoans, land plants, angiosperms (flowering plants), or euteleostomi (bony vertebrates ), consistent with well-established TF expansions in these lineages (de Mendoza et al., 2013; Weirauch and Hughes, 2011). "
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    • "ARFs can have overlapping (Ellis et al., 2005; Nagpal et al., 2005; Okushima et al., 2005), (Rademacher et al., 2011), different (Rademacher et al., 2012; Rademacher et al., 2011; Weijers et al., 2005), or even opposing (Rademacher et al., 2011) functions, and an important question is how these different activities are encoded in their structures. Often, in the Homeodomain family (Berger et al., 2008; Noyes et al., 2008), for example, variation in sequence-specific DNA binding in transcription factor families is generated by substitutions in the DNA-contacting residues. In contrast, intrinsic DNA-binding specificity among ARF proteins is highly similar, even between the phylogenetically diverse family members ARF1 and ARF5, a finding that is consistent with the limited sequence divergence at the DNA-binding surface. "
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