SALL1 enforces microglia-specific DNA binding and function of SMADs to establish microglia identity

Author:

Fixsen Bethany R.,Han Claudia Z.,Zhou Yi,Spann Nathanael J.,Saisan Payam,Shen Zeyang,Balak ChristopherORCID,Sakai MashitoORCID,Cobo Isidoro,Holtman Inge R.,Warden Anna S.,Ramirez Gabriela,Collier Jana G.,Pasillas Martina P.,Yu Miao,Hu Rong,Li Bin,Belhocine Sarah,Gosselin DavidORCID,Coufal Nicole G.ORCID,Ren Bing,Glass Christopher K.ORCID

Abstract

AbstractSpalt-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 theSall1promoter results in complete and specific loss ofSall1expression in microglia. By determining the genomic binding sites of SALL1 and leveragingSall1enhancer knockout mice, we provide evidence for functional interactions between SALL1 and SMAD4 required for microglia-specific gene expression. SMAD4 binds directly to theSall1super-enhancer and is required forSall1expression, consistent with an evolutionarily conserved requirement of the TGFβ and SMAD homologsDppandMadfor cell-specific expression ofSpaltin theDrosophilawing. 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.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke

Cure Alzheimer’s Fund

JPB Foundation

U.S. Department of Health & Human Services | NIH | National Institute on Aging

U.S. Department of Health & Human Services | NIH | National Institute of Mental Health

Publisher

Springer Science and Business Media LLC

Subject

Immunology,Immunology and Allergy

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