Comparison of PU.1 genomic binding across immune cells reveals cell type-specific roles in autoimmune disease

Transcription factors play key roles in cellular biology. Their genomic binding events are enriched at disease- and trait-associated genetic risk loci in particular cellular contexts. To examine this phenomenon in depth, we constructed a PU.1 (SPI1) binding atlas by uniformly processing 260 PU.1 ChIP-seq datasets spanning many immune cell types. Comparison of ChIP-seq peaks across eight major immune cell types identifies shared and cell type-specific PU.1 binding events. DNA sequence analyses reveals context-specific binding shaped by both canonical PU.1 motifs and motifs from partner transcription factor families. Integration of this atlas with genome-wide association studies of blood cell traits and immune-mediated diseases reveals strong enrichment for PU.1 binding events at genetic risk loci and extensive genotype-dependent PU.1 genomic occupancy. We identify cellular contexts in which PU.1 enrichment is most pronounced, including at autoimmune disease loci within EBV-positive B cells. Together, these results define cellular, infectious, and genetic contexts of PU.1 binding that help connect noncoding variation to human phenotypes.