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Iterative transcription factor screening enables rapid generation of microglia-like cells from human iPSC -Single cell transcriptome timecourse analysis of TFiMGLs after SCF-MCI (SPI1, FLI1, CEBPA, CEBPB, IRF8, and Mef2C) induction.

ABSTRACT: Transcription factor (TF) screens have enabled efficient production of a few cell types; however, engineering cell types that require complex TF combinations remains challenging. Here, we report an iterative, high-throughput single-cell TF screening method that enables identification of TF combinations for specialized cell differentiation, which we validated by differentiating human microglia-like cells. We found that the expression of six TFs, SPI1, CEBPA, FLI1, MEF2C, CEBPB, and IRF8, is sufficient to differentiate human iPSC into cells with transcriptional and functional similarity to primary human microglia within 4 days.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287852 | GEO | 2025/03/23

REPOSITORIES: GEO

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Iterative transcription factor screening enables rapid generation of microglia-like cells from human iPSC - TFiMGLs are responsive to disease-relevant stimuli

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A dual cis-regulatory code links IRF8 to constitutive and inducible gene expression in macrophages.

Project description:IThe transcription factor (TF) interferon regulatory factor 8 (IRF8) controls both developmental and inflammatory stimulus-inducible genes in macrophages, but the mechanisms underlying these two different functions are largely unknown. One possibility is that these different roles are linked to the ability of IRF8 to bind alternative DNA sequences. We found that IRF8 is recruited to distinct sets of DNA consensus sequences before and after lipopolysaccharide (LPS) stimulation. In resting cells, IRF8 was mainly bound to composite sites together with the master regulator of myeloid development PU.1. Basal IRF8–PU.1 binding maintained the expression of a broad panel of genes essential for macrophage functions (such as microbial recognition and response to purines) and contributed to basal expression of many LPS-inducible genes. After LPS stimulation, increased expression of IRF8, other IRFs, and AP-1 family TFs enabled IRF8 binding to thousands of additional regions containing low-affinity multimerized IRF sites and composite IRF–AP-1 sites, which were not premarked by PU.1 and did not contribute to the basal IRF8 cistrome. While constitutively expressed IRF8-dependent genes contained only sites mediating basal IRF8/PU.1 recruitment, inducible IRF8-dependent genes contained variable combinations of constitutive and inducible sites. Overall, these data show at the genome scale how the same TF can be linked to constitutive and inducible gene regulation via distinct combinations of alternative DNA-binding sites.

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