Excited to share a story about mutations in the IRF4 TF DNA binding domain that alter its binding specificity to cause a dominant form of immunodeficiency. Great work led by @TurveyLab https://www.science.org/doi/10.1126/sciimmunol.ade7953 1/12

The work reflects a virtuoso bioinformatics effort by @ofornes that started for us with an email about a single amino acid change in IRF4 that was observed in a child with immune problems 2/12

IRF4 DNA binding is complex as it partners with many different TFs for binding. On its own IRF4 binds to ISRE motifs, but in partnership targets composite sites - EICEs (ETS partnered) and AICEs (AP1 partnered) 3/12

After structural modeling, @ofornes suggested that the introduction of a positively charged amino acid at the position could cause increased DNA affinity, which would alter TF-DNA interactions 4/12

In an amazing effort spanning many countries and disciplines, more patients were discovered and extensive profiling of mutant IRF4 binding was generated – so many partners stepped up 5/12

to show that the mutations were indeed causing IRF4 to stick to a much broader range of DNA sequences 6/12

The binding data showed in particular that the mutation was allowing the TF to stick to novel target sequences, most strikingly those having a GATA instead of a GATA in the motif 7/12

Pulling together the diverse types of binding data compiled, @ofornes used our ExplaiNN system (with input from @NovakovskyG ) to explore the relative contribution of the diverse IRF4 target sites observed … 8/12
https://www.biorxiv.org/content/10.1101/2022.05.20.492818v3

ExplaiNN provided great insight into the wide range of IRF4 binding motifs, returning Importance scores that clearly highlight the novel motifs targeted by IRF4 9/12