SPI1 encodes PU.1, a transcription factor essential for the development and function of myeloid cells. We hypothesize that it may modulate AD risk by regulating the transcription of AD-associated genes expressed in microglia and/or other myeloid cell types. First, we tested AD-associated genes for evidence of expression in human microglia29 as well as presence of PU.1 binding peaks in cis-regulatory elements of these genes using ChIP-Seq datasets obtained from human monocytes and macrophages35. We specifically investigated 112 AD-associated genes, including the 104 genes located within IGAP GWAS loci36 and APOE, APP, TREM2 and TREML2, TYROBP, TRIP4, CD33, and PLD3. Among these genes, 75 had evidence of gene expression in human brain microglial cells, 60 of which also had evidence of association with PU.1 binding sites in human blood myeloid cells35 (Supplementary Table 11). Further examination of PU.1 binding peaks and chromatin marks/states in human monocytes confirmed that PU.1 is bound to cis-regulatory elements of many AD-associated genes, including ABCA7, CD33, MS4A4A, MS4A6A, PILRA, PILRB, TREM2, TREML2, and TYROBP (as well as SPI1 itself, but notably not APOE) (Fig. 2c, Supplementary Fig. 7). Together, these results suggest that PU.1 may regulate the expression of multiple AD-associated genes in myeloid cells.
