BACH1 recruits NANOG and histone H3 lysine 4 methyltransferase MLL/SET1 complexes to regulate enhancer–promoter activity and maintains pluripotency

Abstract

Maintenance of stem-cell identity requires proper regulation of enhancer activity. Both transcription factors OCT4/SOX2/NANOG and histone methyltransferase complexes MLL/SET1 were shown to regulate enhancer activity, but how they are regulated in embryonic stem cells (ESCs) remains further studies. Here, we report a transcription factor BACH1, which directly interacts with OCT4/SOX2/NANOG (OSN) and MLL/SET1 methyltransferase complexes and maintains pluripotency in mouse ESCs (mESCs). BTB domain and bZIP domain of BACH1 are required for these interactions and pluripotency maintenance. Loss of BACH1 reduced the interaction between NANOG and MLL1/SET1 complexes, and decreased their occupancy on chromatin, and further decreased H3 lysine 4 trimethylation (H3K4me3) level on gene promoters and (super-) enhancers, leading to decreased enhancer activity and transcription activity, especially on stemness-related genes. Moreover, BACH1 recruited NANOG through chromatin looping and regulated remote NANOG binding, fine-tuning enhancer–promoter activity and gene expression. Collectively, these observations suggest that BACH1 maintains pluripotency in ESCs by recruiting NANOG and MLL/SET1 complexes to chromatin and maintaining the trimethylated state of H3K4 and enhancer–promoter activity, especially on stemness-related genes.

The transcription factor BACH1 at the crossroads of cancer biology: From epithelial–mesenchymal transition to ferroptosis

“…The BTB domain of the zinc finger protein BCL6 mediates interaction with corepressors as well ( 33 ). The BTB domain of BACH1 is also bound by ubiquitin E3 ligase adaptor proteins ( 34 , 35 ), and the BACH1 BTB domain directly binds to NANOG ( 36 ).…”

“…BACH1 may cooperate with HOXB8 to induce the expression of their shared target genes. BACH1 interacts directly with the MLL complex that catalyzes the trimethylation of histone H3 lysine 4 and is required for the expression of a set of BACH1 target genes ( 36 ). Cancer cells may utilize such an interaction to convert BACH1 into an activator.…”

KDM5A suppresses PML-RARα target gene expression and APL differentiation through repressing H3K4me2

“…Chromatin immunoprecipitation (ChIP) was performed as previously descripted. 31 For histone modifications, 3 3 10 6 cells per IP and 2 mg of primary antibodies were used; for KMD5A ChIP, 4 32 Differential peaks were identified by DiffBind. 33 ChIP-seq heatmaps and density plots were drawn by ngsplot.…”

p53 inactivation unmasks histone methylation-independent WDR5 functions that drive self-renewal and differentiation of pluripotent stem cells

“…Lefty1 and Lefty2 , among the 30 WDR5 WT direct target genes, have been reported to balance ESC self-renewal and differentiation ( Kim et al., 2014a ) ( Figure 2 F). Prdm14 , Lin28b , and Bach1 , among the 64 WDR5 S91K−Y191F direct target genes, regulate PSC reprogramming and chromatin maintenance ( Nady et al., 2015 ; Niu et al., 2021 ; Shyh-Chang and Daley, 2013 ) ( Figure 2 F). Collectively, these data indicate that, by targeting distinct loci compared with WDR5 WT , which are largely devoid of H3K4me3, WDR5 S91K−Y191F rewires the WDR5-chromatin interaction in an H3K4 methylation-independent manner and regulates target gene expression in p53 -null mESCs.…”