SALL1 enforces microglia-specific DNA binding and function of SMADs to establish microglia identity
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説明
<jats:title>Abstract</jats:title><jats:p>Spalt-like transcription factor 1 (SALL1) is a critical regulator of organogenesis and microglia identity. Here we demonstrate that disruption of a conserved microglia-specific super-enhancer interacting with the<jats:italic>Sall1</jats:italic>promoter results in complete and specific loss of<jats:italic>Sall1</jats:italic>expression in microglia. By determining the genomic binding sites of SALL1 and leveraging<jats:italic>Sall1</jats:italic>enhancer knockout mice, we provide evidence for functional interactions between SALL1 and SMAD4 required for microglia-specific gene expression. SMAD4 binds directly to the<jats:italic>Sall1</jats:italic>super-enhancer and is required for<jats:italic>Sall1</jats:italic>expression, consistent with an evolutionarily conserved requirement of the TGFβ and SMAD homologs<jats:italic>Dpp</jats:italic>and<jats:italic>Mad</jats:italic>for cell-specific expression of<jats:italic>Spalt</jats:italic>in the<jats:italic>Drosophila</jats:italic>wing. Unexpectedly, SALL1 in turn promotes binding and function of SMAD4 at microglia-specific enhancers while simultaneously suppressing binding of SMAD4 to enhancers of genes that become inappropriately activated in enhancer knockout microglia, thereby enforcing microglia-specific functions of the TGFβ–SMAD signaling axis.</jats:p>
収録刊行物
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- Nature Immunology
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Nature Immunology 24 1188-1199, 2023-06-15
Springer Science and Business Media LLC