Sustained TNF-α stimulation induces transcriptional memory that greatly enhances signal sensitivity and robustness

  1. Zuodong Zhao
  2. Zhuqiang Zhang
  3. Jingjing Li
  4. Qiang Dong
  5. Jun Xiong
  6. Yingfeng Li
  7. Mengying Lan
  8. Gang Li
  9. Bing Zhu  Is a corresponding author
  1. Chinese Academy of Sciences, China
  2. University of Macau, China

Abstract

Transcriptional memory allows certain genes to respond to previously experienced signals more robustly. However, whether and how the key proinflammatory cytokine TNF-α mediates transcriptional memory are poorly understood. Using HEK293F cells as a model system, we report that sustained TNF-α stimulation induces transcriptional memory dependent on TET enzymes. The hypomethylated status of transcriptional regulatory regions can be inherited, facilitating NF-κB binding and more robust subsequent activation. A high initial methylation level and CpG density around κB sites are correlated with the functional potential of transcriptional memory modules. Interestingly, the CALCB gene, encoding the proven migraine therapeutic target CGRP, exhibits the best transcriptional memory. A neighboring primate-specific endogenous retrovirus stimulates more rapid, more strong and at least 100-fold more sensitive CALCB induction in subsequent TNF-α stimulation. Our study reveals that TNF-α-mediated transcriptional memory is governed by active DNA demethylation and greatly sensitizes memory genes to much lower doses of inflammatory cues.

Data availability

All high-throughput data generated in this study have been deposited in NCBI GEO database under accession number GSE152146, except that p65 ChIP-seq data for 0 h and 12 h TNF-α treatments have been deposited under the accession number GSE121361 (Zhao et al., 2019).

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Zuodong Zhao

    Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Zhuqiang Zhang

    Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6513-2854
  3. Jingjing Li

    Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Qiang Dong

    Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Jun Xiong

    Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Yingfeng Li

    Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Mengying Lan

    Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Gang Li

    Faculty of Health Sciences, University of Macau, Taipa, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3203-8567
  9. Bing Zhu

    Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    For correspondence
    zhubing@ibp.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2049-432X

Funding

the Chinese ministry of Science and technology (2018YFE0203300)

  • Bing Zhu

the national natural science foundation of China (31530047)

  • Bing Zhu

the national natural science foundation of China (31761163001)

  • Bing Zhu

Chinese Academy of Sciences (XDB 39000000)

  • Bing Zhu

Chinese Academy of Sciences (QYZDY-SSW-SMC031)

  • Bing Zhu

Youth Innovation Promotion Association of the Chinese Academy of Sciences (2017133)

  • Zhuqiang Zhang

Youth Innovation Promotion Association of the Chinese Academy of Sciences (2020097)

  • Jun Xiong

the NSFC-FDCT joint grant (31761163001)

  • Bing Zhu

the NSFC-FDCT joint grant (033/2017/AFJ)

  • Gang Li

This work was supported by the Chinese Ministry of Science and Technology (2018YFE0203300), the NSFC-FDCT joint grant (31761163001 for B.Z and 033/2017/AFJ for G.L.), the National Natural Science Foundation of China (31530047, 31761163001), and the Chinese Academy of Sciences (XDB 39000000 and QYZDY-SSW-SMC031). Z. Zhang and J.X. are supported by the Youth Innovation Promotion Association (2017133 and 2020097, respectively) of the Chinese Academy of Sciences.

Reviewing Editor

  1. Xiaobing Shi, Van Andel Institute, United States

Version history

  1. Received: August 10, 2020
  2. Accepted: November 5, 2020
  3. Accepted Manuscript published: November 6, 2020 (version 1)
  4. Version of Record published: November 30, 2020 (version 2)

Copyright

© 2020, Zhao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,871
    views
  • 799
    downloads
  • 27
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Zuodong Zhao
  2. Zhuqiang Zhang
  3. Jingjing Li
  4. Qiang Dong
  5. Jun Xiong
  6. Yingfeng Li
  7. Mengying Lan
  8. Gang Li
  9. Bing Zhu
(2020)
Sustained TNF-α stimulation induces transcriptional memory that greatly enhances signal sensitivity and robustness
eLife 9:e61965.
https://doi.org/10.7554/eLife.61965

Share this article

https://doi.org/10.7554/eLife.61965

Further reading

    1. Chromosomes and Gene Expression
    2. Developmental Biology
    F Javier DeHaro-Arbona, Charalambos Roussos ... Sarah Bray
    Research Article

    Developmental programming involves the accurate conversion of signalling levels and dynamics to transcriptional outputs. The transcriptional relay in the Notch pathway relies on nuclear complexes containing the co-activator Mastermind (Mam). By tracking these complexes in real time, we reveal that they promote the formation of a dynamic transcription hub in Notch ON nuclei which concentrates key factors including the Mediator CDK module. The composition of the hub is labile and persists after Notch withdrawal conferring a memory that enables rapid reformation. Surprisingly, only a third of Notch ON hubs progress to a state with nascent transcription, which correlates with polymerase II and core Mediator recruitment. This probability is increased by a second signal. The discovery that target-gene transcription is probabilistic has far-reaching implications because it implies that stochastic differences in Notch pathway output can arise downstream of receptor activation.

    1. Cancer Biology
    2. Chromosomes and Gene Expression
    Gregory Caleb Howard, Jing Wang ... William P Tansey
    Research Article

    The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the ‘WIN’ site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.