ZFR suppresses the antiviral response, but not in ME? Is macroH2A1/H2AFY involved?

ME peripheral blood mononuclear cell (PBMC) proteomes reveal decreased level of zinc finger RNA-binding protein (ZFR), foldchange = 0,52, p-value = 0,00047 (1).

ZFR suppresses interferon-beta induction and the antiviral response. ZFR controls interferon signaling by preventing aberrant splicing and nonsense-mediated decay (NMD) of histone variant macroH2A1/H2AFY mRNAs (2).

Serum from ME patients contains an activity which induces a powerful antiviral state, but it seems like the interferon response has been ruled out in the ME pathomechanism (3, 4).

However, macroH2A1 has also been shown to bind and repress interferon-stimulated genes (ISG) promoters, raising the possibility that the constitutive ISG induction in ZFR-depleted cells could be partially due to loss of direct action of macroH2A1 on these genes. Taking the available data together, macroH2A1 appears to both suppress the initiation of type I interferon signaling by inhibiting IFNB1 transcription and by modulating the consequences of IFNB1 transcription by directly repressing ISG promoters (2).

The gene macroH2A1/H2AFY is differentially methylated in PBMC from ME patients. Read the blogpost:

H2AFY and ME

https://followmeindenmark.blogspot.com/2018/10/h2afy-and-me.html

Is dysregulated macroH2A1/H2AFY involved in the ME pathomechanism?

MacroH2A1 can buffer transcriptional noise associated with the antiviral response

Knockdown of macroH2A causes a dramatic change in the antiviral gene expression program. Genes that normally do not respond to virus infection get activated or repressed (5).

References

preprint 1) Eiren Sweetman, Torsten Kleffmann, Christina Edgar, Michel de Lange, Rosamund Vallings Howick Warren Tate: A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction
https://assets.researchsquare.com/files/rs-52172/v1/6b319d19-80fb-46e3-b56e-3687ae1c7203.pdf

2) Haque N, Ouda R, Chen C, Ozato K, Hogg JR. ZFR coordinates crosstalk between RNA decay and transcription in innate immunity. Nat Commun. 2018;9(1):1145. Published 2018 Mar 20. doi:10.1038/s41467-018-03326-5
https://www.nature.com/articles/s41467-018-03326-5

3) Schreiner P, Harrer T, Scheibenbogen C, et al. Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Immunohorizons. 2020;4(4):201-215. Published 2020 Apr 23. doi:10.4049/immunohorizons.2000006
https://pubmed.ncbi.nlm.nih.gov/32327453/

4) Corbitt M, Eaton-Fitch N, Staines D, Cabanas H, Marshall-Gradisnik S. A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID). BMC Neurol. 2019;19(1):207. Published 2019 Aug 24. doi:10.1186/s12883-019-1433-0

5) Lavigne MD, Vatsellas G, Polyzos A, et al. Composite macroH2A/NRF-1 Nucleosomes Suppress Noise and Generate Robustness in Gene Expression. Cell Rep. 2015;11(7):1090-1101. doi:10.1016/j.celrep.2015.04.022