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KDM6B-dependent chromatin remodelling underpins effective virus-specific CD8+ T cell differentiation

Jasmine Li, Kristine Hardy, Moshe Olshansky, Adele Barugahare, Linden J. Gearing, Julia E. Prier, Xavier Y.X. Sng, Michelle Ly Thai Nguyen, Dana Piovesan, Brendan Russ, Nicole L. La Gruta, Paul J. Hertzog, Sudha Rao, Stephen J. Turner

Preprint posted on February 05, 2020 https://www.biorxiv.org/content/10.1101/2020.02.03.933218v1

Unleash the chromatin! Global loss of methylation is essential for effective T cell responses

Selected by Jonny Coates

Context and background

The central dogma in biology (DNA -> RNA -> Protein) relies on a highly complex regulation at each individual step. Chromatin accessibility represents one such layer of regulation, influencing the transcription of DNA to RNA (Fig. 1).  The building blocks of chromatin are the histones, which form nucleosomes that wrap DNA. Methylation of histones at specific sites can increase or decrease the wrapping of DNA, with methylation at different sites being known as activating or repressive marks. For example, H3K27me3 is a repressive mark that indicates closed chromatin and a decrease in transcription.

Figure 1. The histone code and histone modification nomenclature. Histones can be modified by “writer” or “eraser” enzymes and can be read by “reader” enzymes (not depicted here). The different features shown are the type of histone (H3 in this example), the amino acid and its position (here, Lysine at position 27) and the chemical modification (a trimethylation).

Immune cells are capable of rapidly responding to external stimuli and generating diverse transcriptional and proteome profiles. To perform such rapid functions, immune cells rely on modifying the regulatory mechanisms that control transcription and translation. For example, it has previously been demonstrated that there are extensive epigenetic changes in T cells following their activation (1). T-cells are essential for the removal of virally-infected cells and tumours. Moreover, T-cells form an essential component of immunological memory which enables much quicker and more precise responses to secondary infection. In this preprint, Li et al demonstrate that upon activation of the T-cell receptor (TCR) there is a global loss of a specific methylation on histone 3 which is essential for subsequent T-cell responses

 

Key findings

  1. Upon TCR stimulation, there is a global loss of H3K27me3

The authors stimulated T cells and performed RNAseq over multiple time points. They found a number of histone methyltransferases to be up-regulated but only one demethylase (KDM6B) which removes the methylation of H3K27) that was up-regulated. Interestingly, KDM6B was found to increase within 1 hour of stimulation and remained so until 24-hours post-stimulation. Indeed, as the time post-stimulation increased, the levels of H3K27me3 decreased and the chromatin became more accessible (as shown with H3 ChIP-qPCR). Transcription of associated genes increased over this period as transcription factors were now able to bind to their target genes, confirming a direct role of H3K27me3 loss in driving effector T cell functions. More importantly, the authors demonstrated that there was a global loss of H3K27me3 and that this occurred very rapidly (within 3 hours of stimulation).

 

  1. Loss of H3K27me3 is essential for appropriate primary responses and the formation of immunological memory

To determine the effect that H3K27me3 loss was having on T cell functions, the authors utilised a small molecule inhibitor of KDM6B, GSK-J4. By preventing the activity of KDM6B, the H3K27me3 modification can’t be removed. By inhibiting KDM6B, the authors found that cells underwent fewer divisions, indicating that loss of H3K27me3 was required for cell proliferation and expansion. When the authors looked in vivo, they found that there was a significantly reduced primary response by T-cells treated with GSK-J4. Surprisingly, this failure to remove the H3K27me3 modification also affected the secondary memory response.

 

Why I chose this paper

This work is relatively close to my current research. The role of epigenetic modifications in the immune system is becoming an increasingly important area of research. This paper clearly illustrates the importance of epigenetic changes and how these drive immune cell functions. I was particularly surprised by how quickly these changes are occurring and the longevity of their effects – lasting right through to a memory response!

 

Open questions

  1. Is the lack of a memory response a result of the poor primary response or is it more directly related to the drug treatment which prevented the loss of H3K27me3? For example, if the J4 drug was used after the primary response would this reduce the memory/secondary response?
  2. The authors analysed multiple histone demethylase enzymes at the transcriptional level. However, were there any analyses performed at the protein level? Is it possible that some of the other enzymes are modified at the protein level but not transcriptionally?
  3. Did the authors assess the activity of the histone demethylase enzymes? Was TCR stimulation changing the activity levels of these enzymes? Again, this could potentially reveal other enzymes besides KDM6B with altered behaviour that are not regulated at the transcriptional level.
  4. The authors demonstrate that stimulation of the TCR with peptide induces KDM6B up-regulation. Could the authors speculate what they believe is causing this upregulation (i.e. what is binding to the KDM6B gene)? For example, it has previously been shown that AP-1 is required for the opening of chromatin following TCR-stimulation (1).
  5. It appears that T cells treated with J4 are unable to survive well or proliferate. Are there wider effects on immune functions, such as granzyme release or IFN-γ production?

 

References

  1. Yukawa M, Jagannathan S, Vallabh S, Kartashov AV, Chen X, Weirauch MT, et al. AP-1 activity induced by co-stimulation is required for chromatin opening during T cell activation. J Exp Med 2020 Jan 6;217(1).

Tags: cell biology, chromatin, epigenetics, h3k27me3, histone modifications, immune memory, immune response, immunology, kdm6b

Posted on: 19th February 2020

doi: https://doi.org/10.1242/prelights.16812

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