PU.1 binds to cis-regulatory elements of several AD-associated genes expressed in human myeloid cells, including ABCA7, CD33, MS4A4A, MS4A6A, TREM2, and TYROBP (Fig. 1e, Supplementary Fig. 7). Further, PU.1 binds to active enhancers of Trem2 and Tyrobp in ChIP-Seq experiments using mouse BV2 cells42 or bone marrow-derived mouse macrophages43. PU.1 is required for the development and function of myeloid and B-lymphoid cells44,45. In particular, PU.1 expression is dynamically and tightly controlled during haematopoiesis to direct the specification of CD34+ hematopoietic stem and progenitor cells toward the myeloid and B-lymphoid lineage by progressively partitioning into CD14+ monocytes/macrophages, CD15+ neutrophils, and CD19+ B cells46, which are the cell types highlighted by our stratified LD score regression analysis. Given its selective expression in microglia in the brain (Fig. 2b), PU.1 may modify microglial cell function through transcriptional regulation of target genes that act as downstream modulators of AD susceptibility, as evidenced by the significant enrichment of AD heritability partitioned on the PU.1 cistrome in human myeloid cells (Supplementary Table 12).
