H2AFY and ME

H2AFY (also known as macroH2A1) is a histone H2A variant. It replaces conventional H2A histones in a subset of nucleosomes.

This gene encodes two splice isoforms, H2AFY1.1 and H2AFY1.2 (also known as mH2A1.1 and mH2A1.2). mH2A1.1 and mH2A1.2 are produced by mutually exclusive use of exons 6b and 6a.  The isoforms have distinct regulatory properties.

H2AFY, ZFR and interferon signaling

ZFR (zinc finger RNA binding protein)  coordinates crosstalk between RNA decay and transcription in innate immunity.

ZFR protein is required for H2AFY expression. ZFR regulates alternative splicing and decay of H2AFY mRNA.

ZFR controls interferon signaling by preventing aberrant splicing and nonsense-mediated decay of histone variant macroH2A1/H2AFY mRNAs (1).

Figure from reference 1: Model for ZFR-mediated regulation of IFNβ. ZFR is required for productive splicing of mH2A1. In the absence of ZFR, mH2A1 pre-mRNA is mis-spliced and resulting transcript is degraded by NMD. In the presence of ZFR, mH2A1 protein is expressed and directly represses the IFNB1 promoter (1).

MacroH2A1.1 regulates mitochondrial respiration

MacroH2A1.1 contains a macrodomain capable of binding NAD+-derived metabolites.

MacroH2A1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing, and  myotubes that lack macroH2A1.1 have a defect in mitochondrial respiratory capacity (2).

H2AFY and B-cells

The H2AFY1.1 isoform is important for B cell development. Reduction in this isoform may contribute to abnormal hematopoiesis (3).

H2AFY in ME

DNA methylation pattern in the gene H2AFY in peripheral blood mononuclear cells (PBMC) from ME patients:

de Vega 2017(table S7 in ref 4): TSS200, TSS1500 and body are hypermethylated

de Vega 2018 (table S3 in ref 5): Five different probes (rank 96, 229, 277, 711 and 965) show the gene is differentially methylated in ME patients subtypes

Trivedi 2018 (table S6 in ref 6): The gene promoter is hypomethylated

Trivedi 2018 (table S4 in ref 6): Thirteen different probes show that TSS1500 and 3'UTR are hypomethylated

Why is H2AFY hypermethylated in de Vega's study and hypomethylated in Trivedi's study?

H2AFY isoform 2 content in cerebrospinal fluid (7):
1) Controls: no value
2) ME patients: 3
3) Post treatment Lyme patients: 5

What does H2AFY do in ME?

References: 

1) Hauque et al. ZFR coordinates crosstalk between RNA decay and transcription in innate immunity. Nature Communicationsvolume 9, Article number: 1145 (2018)

https://www.nature.com/articles/s41467-018-03326-5
Figure: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861047/figure/Fig7/

2)  Marjanovic et al. MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption. Nature Structural & Molecular Biology,  volume 24, pages902–910 (2017)
https://www.nature.com/articles/nsmb.3481

3) Sanghyun Kim, Monique Chavez, Cara Shirai and Matt Walter. Abstract 5108: The role of H2afy in normal and malignant hematopoiesis.  DOI: 10.1158/1538-7445.AM2018-5108 Published July 2018 http://cancerres.aacrjournals.org/content/78/13_Supplement/5108.short

4) de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324230/

5) de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015

6) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns.

 Plos One 2018, 13, 7   https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066

7) Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issue  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017287