How do transcription factors regulate gene expression?
Transcription factors bind DNA with DNA binding domains, bind corepressor complexes with repression domains and coactivator complexes with activation domains. DNA binding domains are structured, conserved and well understood. Activation domains are intrinsically disordered, poorly conserved and poorly understood.
Sequence features of activation domains
What are the amino acid sequence features that control the function of activation domains? We design thousands of activation domain variants and measure the activities of these variants with high throughput assays.
Predicting different types of activation domains
We aim to understand the different types of activation domains, which coactivators they bind, and what steps of transcription they control. We use machine learning to predict activation domains from protein sequence.
Transcription factor evolution
Outside of the DNA binding domain, most transcription factors have low conservation of primary amino acid sequence, but overall transcription factor function is maintained over large evolutionary distances. We are investigating this conservation of function without conservation of primary sequence.
Variants of Uncertain Significance
Precision medicine requires detailed diagnosis and targeted therapies. We are working to improve diagnoses. Most variants found in clinical sequencing samples are labeled as Variants of Uncertain Significance (VUS) because their pathogenicity or functional effects are unknown. By characterizing the molecular functions of VUS in activation domains, we aim to improve the detailed diagnoses required for targeted cancer therapies.