Fig. 4

FDAMic evolved from female ARMic associated with a compromised estrogen receptor signaling network. A Transcription regulons that possibly regulated the DEGs in all subtypes of microglia were predicted by the SCENIC algorithm. Their degrees of activation are indicated by the color. B Dot plot showing the relative expression levels of ESR1 and ESR2 in different subtypes of microglia. C Left (STRING network): physical interaction network between ESR1/ERα and the 4 sets of transcription regulons identified by the SCENIC algorithm. Transcription factor labels indicate positive interactions. Right (heatmap): physical binding prediction between transcription factors predicted with ESR1/ERα or ESR2/ERβ. D Random permutation of transcription factors (TFs) and their probabilities of interacting with ESR1/ERα. On average, 12 out of 55 (probability = 0.22) randomly selected TFs may interact with ESR1/ERα; this is in stark contrast to 33 out of 55 (probability = 0.6) identified from the SCENIC algorithm. E Heatmap showing the scaled gene expression level of ESR1/ERα-targeted TFs in different subclusters of microglia. F Functional enrichment analysis of the 288 SPI1 target genes highly expressed in microglia. G, H Correlations between the normalized expression level of SPI1/PU.1 and those of various G MHC class II autoantigens or H cell proliferation-associated genes. All of these are downstream targets of SPI1/PU.1. I Top: volcano plot showing DEGs identified from the comparison between ARMic of female versus male origins. Key microglial MHC autoantigens and proliferation-associated genes are labeled. Bottom: violin plots illustrating the expression profiles of these key genes across all subtypes of microglia