BRG1 Governs Nanog Transcription in Early Mouse Embryos and Embryonic Stem Cells via Antagonism of Histone H3 Lysine 9/14 Acetylation.

During mouse preimplantation development, the generation of the inner cell mass (ICM) and trophoblast lineages comprises upregulation of Nanog expression in the ICM and its silencing in the trophoblast. However, the underlying epigenetic mechanisms that differentially regulate Nanog in the first cell lineages are poorly understood. Here, we report that BRG1 (Brahma-related gene 1) cooperates with histone deacetylase 1 (HDAC1) to regulate Nanog expression. BRG1 depletion in preimplantation embryos and Cdx2-inducible embryonic stem cells (ESCs) revealed that BRG1 is necessary for Nanog silencing in the trophoblast lineage. Conversely, in undifferentiated ESCs, loss of BRG1 augmented Nanog expression. Analysis of histone H3 within the Nanog proximal enhancer revealed that H3 lysine 9/14 (H3K9/14) acetylation increased in BRG1-depleted embryos and ESCs. Biochemical studies demonstrated that HDAC1 was present in BRG1-BAF155 complexes and BRG1-HDAC1 interactions were enriched in the trophoblast lineage. HDAC1 inhibition triggered an increase in H3K9/14 acetylation and a corresponding rise in Nanog mRNA and protein, phenocopying BRG1 knockdown embryos and ESCs. Lastly, nucleosome-mapping experiments revealed that BRG1 is indispensable for nucleosome remodeling at the Nanog enhancer during trophoblast development. In summary, our data suggest that BRG1 governs Nanog expression via a dual mechanism involving histone deacetylation and nucleosome remodeling.

Carey TS ，Cao Z ，Choi I ，Ganguly A ，Wilson CA ，Paul S ，Knott JG ... -  《-》

Transcriptional reprogramming and chromatin remodeling accompanies Oct4 and Nanog silencing in mouse trophoblast lineage.

Carey TS ，Choi I ，Wilson CA ，Floer M ，Knott JG ... -  《-》

De-regulated expression of the BRG1 chromatin remodeling factor in bone marrow mesenchymal stromal cells induces senescence associated with the silencing of NANOG and changes in the levels of chromatin proteins.

Squillaro T ，Severino V ，Alessio N ，Farina A ，Di Bernardo G ，Cipollaro M ，Peluso G ，Chambery A ，Galderisi U ... -  《-》

Brg1 is required for Cdx2-mediated repression of Oct4 expression in mouse blastocysts.

Wang K ，Sengupta S ，Magnani L ，Wilson CA ，Henry RW ，Knott JG ... -  《PLoS One》

SWI/SNF-Brg1 regulates self-renewal and occupies core pluripotency-related genes in embryonic stem cells.

Kidder BL ，Palmer S ，Knott JG 《-》