MAGGIE

MAGGIE identifies DNA sequence motifs that mediate transcription factor binding and function by associating motif mutations arising from genetic variation with changes in epigenomic features to understand how regulatory variation affects TF activity.

Key Features:

• Motif–variation association: Associates mutations in transcription factor binding motifs with changes in epigenomic features.
• Epigenomic features analyzed: Analyzes transcription factor binding, open chromatin regions, histone modifications, and stimulus-responsive regulatory element activity.
• Genetic variation sources: Leverages genetic variation across diverse genotypes including human individuals, animal strains, and alleles.
• Statistical approach: Employs a novel statistical method that does not assume a linear relationship between motif mutation and functional outcome.
• Performance improvements: Enhances sensitivity and specificity in identifying motifs that mediate TF binding and function compared with existing methods.
• Benchmarking: Validated using simulated and biological datasets.

Scientific Applications:

• TF functional dissection: Revealed distinct functions of NF-κB factors in pro-inflammatory macrophages.
• Regulatory variant interpretation: Links genetic variation in regulatory elements to changes in TF binding, chromatin accessibility, histone modification, and stimulus response.
• Regulatory landscape exploration: Enables study of how genetic diversity influences gene expression and cellular function.

Methodology:

Associates motif mutations derived from genetic variation across genotypes with changes in epigenomic features (TF binding, chromatin accessibility, histone modifications, stimulus response) using a statistical approach that does not assume linear relationships, with validation on simulated and biological datasets.