The Number of Transcription Factors at an Enhancer Determines Switch-like Gene Expression
Hiroki Michida,
Hiroaki Imoto,
Hisaaki Shinohara,
Noriko Yumoto,
Masahide Seki,
Mana Umeda,
Tetsutaro Hayashi,
Itoshi Nikaido,
Takeya Kasukawa,
Yutaka Suzuki,
Mariko Okada-Hatakeyama
Affiliations
Hiroki Michida
Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan
Hiroaki Imoto
Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan
Hisaaki Shinohara
RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan
Noriko Yumoto
RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan
Masahide Seki
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8568, Japan
Mana Umeda
Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan
Tetsutaro Hayashi
Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan
Itoshi Nikaido
Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan; Functional Genome Informatics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan; Master’s/Doctoral Program in Life Science Innovation (Bioinformatics), Degree Programs in Systems and Information Engineering, Graduate School of Science and Technology, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
Takeya Kasukawa
Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan; RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan
Yutaka Suzuki
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8568, Japan
Mariko Okada-Hatakeyama
Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan; RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan; Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan; Corresponding author
Summary: NF-κB is a transcription factor that activates super enhancers (SEs) and typical enhancers (TEs) and triggers threshold and graded gene expression, respectively. However, the mechanisms by which NF-κB selectively participates in these enhancers remain unclear. Here we show using mouse primary B lymphocytes that SE activity simultaneously associates with chromatin opening and enriched NF-κB binding, resulting in a higher fold change and threshold expression upon B cell receptor (BCR) activation. The higher fold change results from longer DNA, whereas the threshold response is explained by synergy in DNA-NF-κB binding and is supported by the coexistence of PU.1 and NF-κB in a SE before cell stimulation. This model indicates that the pre-existing NF-κB functions as a seed and triggers its processive binding upon BCR activation. Our mathematical modeling of the single-cell transcriptome reveals an additional role for SEs in divergent clonal responses in B cells.
