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The Number of Transcription Factor Molecules Loading at an Enhancer Determines Gene Expression Quantity

45 Pages Posted: 20 Nov 2018 Sneak Peek Status: Under Review

See all articles by Kazunari Iwamoto

Kazunari Iwamoto

Osaka University - Institute for Protein Research

Hisaaki Shinohara

RIKEN Center for Integrative Medical Sciences

Noriko Yumoto

RIKEN Center for Integrative Medical Sciences

Masahide Seki

University of Tokyo, Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences

Mana Umeda

RIKEN Advanced Center for Computing and Communication - Bioinformatics Research Unit

Tetsutaro Hayashi

RIKEN Advanced Center for Computing and Communication - Bioinformatics Research Unit

Itoshi Nikaido

RIKEN Advanced Center for Computing and Communication - Bioinformatics Research Unit; RIKEN Center for Developmental Biology - Single-Cell Omics Research Unit

Yutaka Suzuki

University of Tokyo, Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences

Mariko Okada-Hatakeyama

Osaka University - Institute for Protein Research; RIKEN Center for Integrative Medical Sciences

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Abstract

A single transcription factor (TF) potentially induces both threshold and graded transcription responses via super enhancers (SEs) and typical enhancers (TEs). However, the mechanism by which a TF binds to different types of enhancers to determine gene expression quantity remains to be elucidated. To clarify the mechanism, we performed an integrated analysis of chromatin accessibility, RelA-DNA binding and single-cell transcription for each enhancer in anti-IgM-stimulated mouse primary B lymphocytes. Here we show that SE activity, defined by acetylated histone H3 lysine 27 (H3K27Ac) modifications, was simultaneously quantitatively controlled by chromatin opening and enriched RelA binding, resulting in threshold transcription. Our analysis indicated that the number of RelA binding in open chromatin regions at SEs and TEs was on average five and one, respectively, and that a mathematical model having these differences in TF numbers as parameters could explain enhancer-mediated quantitative transcription differences of individual genes. This study indicates that highly specific on-off expression of TF-enriched SE-targeted genes results in a highly selective epigenetic landscape for cell specificity, in contract to broadly responsive TE-regulated genes that may be responsible for cellular homeostasis.

Suggested Citation

Iwamoto, Kazunari and Shinohara, Hisaaki and Yumoto, Noriko and Seki, Masahide and Umeda, Mana and Hayashi, Tetsutaro and Nikaido, Itoshi and Suzuki, Yutaka and Okada-Hatakeyama, Mariko, The Number of Transcription Factor Molecules Loading at an Enhancer Determines Gene Expression Quantity (November 20, 2018). Available at SSRN: https://ssrn.com/abstract=3287786 or http://dx.doi.org/10.2139/ssrn.3287786
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Kazunari Iwamoto

Osaka University - Institute for Protein Research

3-2 Yamadaoka
Suita
Osaka Prefecture, 565-0871
Japan

Hisaaki Shinohara

RIKEN Center for Integrative Medical Sciences

1-7-22, Suehiro-cho
Tsurumi-ku
Yokohama, Kanagawa
Japan

Noriko Yumoto

RIKEN Center for Integrative Medical Sciences

1-7-22, Suehiro-cho
Tsurumi-ku
Yokohama, Kanagawa
Japan

Masahide Seki

University of Tokyo, Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences

Kashiwa, 277-8568
Japan

Mana Umeda

RIKEN Advanced Center for Computing and Communication - Bioinformatics Research Unit

Wako, Saitama 351-0198
Japan

Tetsutaro Hayashi

RIKEN Advanced Center for Computing and Communication - Bioinformatics Research Unit

Wako, Saitama 351-0198
Japan

Itoshi Nikaido

RIKEN Advanced Center for Computing and Communication - Bioinformatics Research Unit

Wako, Saitama 351-0198
Japan

RIKEN Center for Developmental Biology - Single-Cell Omics Research Unit

Wako, Saitama 351-0198
Japan

Yutaka Suzuki

University of Tokyo, Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences

Kashiwa, 277-8568
Japan

Mariko Okada-Hatakeyama (Contact Author)

Osaka University - Institute for Protein Research ( email )

3-2 Yamadaoka
Suita
Osaka Prefecture, 565-0871
Japan

RIKEN Center for Integrative Medical Sciences ( email )

1-7-22, Suehiro-cho
Tsurumi-ku
Yokohama, Kanagawa
Japan

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