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- Title
Enhanced transcriptional heterogeneity mediated by NF-κB super-enhancers.
- Authors
Wibisana, Johannes N.; Inaba, Takehiko; Shinohara, Hisaaki; Yumoto, Noriko; Hayashi, Tetsutaro; Umeda, Mana; Ebisawa, Masashi; Nikaido, Itoshi; Sako, Yasushi; Okada, Mariko
- Abstract
The transcription factor NF-κB, which plays an important role in cell fate determination, is involved in the activation of super-enhancers (SEs). However, the biological functions of the NF-κB SEs in gene control are not fully elucidated. We investigated the characteristics of NF-κB-mediated SE activity using fluorescence imaging of RelA, single-cell transcriptome and chromatin accessibility analyses in anti-IgM-stimulated B cells. The formation of cell stimulation-induced nuclear RelA foci was abolished in the presence of hexanediol, suggesting an underlying process of liquid-liquid phase separation. The gained SEs induced a switch-like expression and enhanced cell-to-cell variability in transcriptional response. These properties were correlated with the number of gained cis-regulatory interactions, while switch-like gene induction was associated with the number of NF-κB binding sites in SE. Our study suggests that NF-κB SEs have an important role in the transcriptional regulation of B cells possibly through liquid condensate formation consisting of macromolecular interactions. Author summary: NF-κB produces an all-or-none activation response upon the activation of B cell receptors. These dynamics modulate the amplitude and frequency of target mRNA induction in cell populations. In this research, we performed single-cell assessment of chromatin accessibility and RNA expression, coupled with fluorescence imaging to characterize the nuclear dynamics of NF-κB proteins in B cell upon receptor stimulation. We found that upon cellular activation, NF-κB-mediated long-range activation of enhancers cooperatively evoked RNA production. In addition, predicted DNA contacts brought by open chromatin led to the high heterogeneity of RNA levels in cell populations. Stimuli-dependent NF-κB foci formation was further inhibited by 1,6-hexanediol (liquid-liquid phase separation inhibitor) and JQ1 (coactivator protein BRD4 inhibitor). We thus propose that nuclear NF-κB plays an important role in the transcriptional regulation of B cell development possibly through the formation of liquid condensates.
- Subjects
B cell receptors; CELL determination; CELL populations; CELLULAR control mechanisms; B cells; TRANSCRIPTION factors; SUPER enhancers
- Publication
PLoS Genetics, 2022, Vol 18, Issue 6, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1010235