RPS6KB1, EIF4G1 and CD79A in ME/CFS

RPS6KB1 (5'UTR) is the most hypermethylated gene in peripheral blood mononuclear cells (PBMC) from ME patients with a mean beta-difference: 0,353 compared to controls (table S4 in ref 1).

EIF4G1 (body) is the second most hypermethylated gene in PBMC from ME patients (table 2, page 5 in ref 2). EIF4G1 mRNA expression is upregulated in PBMC from ME patients (figure 1 in ref 3).

CD79A is the gene with lowest expression in whole blood from adolescent CFS patients (table S3 in ref 4).

These three gene products interact (5):

Gene Cards STRING Interaction network RPS6KB1 (5)

RPS6KB1: Ribosomal protein S6 kinase, 70kDa, polypeptide 1; Serine/threonine-protein kinase that acts downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression. Regulates protein synthesis through phosphorylation of EIF4B, RPS6 and EEF2K, and contributes to cell survival by repressing the pro-apoptotic function of BAD. Under conditions of nutrient depletion, the inactive form associates with the EIF3 translation initiation complex.

EIF4G1: Eukaryotic translation initiation factor 4 gamma, 1; Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5’-terminal secondary structure and recruitment of mRNA to the ribosome.

CD79A: CD79a molecule, immunoglobulin-associated alpha; Required in cooperation with CD79B for initiation of the signal transduction cascade activated by binding of antigen to the B-cell antigen receptor complex (BCR) which leads to internalization of the complex, trafficking to late endosomes and antigen presentation. Also required for BCR surface expression and for efficient differentiation of pro- and pre-B-cells. Stimulates SYK autophosphorylation and activation. Binds to BLNK, bringing BLNK into proximity with SYK and allowing SYK to phosphorylate BLNK.


SYK and BLNK are also in the RPS6KB1 network (5):

Gene Cards STRING Interaction network CMTM8 (5)


Use the link below to see how the B cell Receptor (BCR) functions with CD79A, SYK and BLNK(6):
https://media.springernature.com/m685/nature-assets/nrd/journal/v12/n3/images/nrd3937-f1.jpg


References:

1) 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

2) 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/

3) Kerr et al:  Assessment of a 44 Gene Classifier for the Evaluation of Chronic Fatigue Syndrome from Peripheral Blood Mononuclear Cell Gene Expression . Plos One 2011 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0016872

4)  Nguyen et al: Whole blood gene expression in adolescent CFS: an exploratory crosssectional study suggesting altered B cell differentiation and survival. J Transl Med. 2017,15,102.  https://www.ncbi.nlm.nih.gov/pubmed/28494812

5) Gene Cards    https://www.genecards.org/

Gene Cards RPS6KB1

Gene Cards CMTM8

6 )Young and Staudt: Targeting pathological B cell receptor signalling in lymphoid malignancies. Nature Reviews Drug Discovery volume12, pages229–243 (2013)
https://www.nature.com/articles/nrd3937

HOX-genes and MIR10A in ME

The genes HOXB3, HOXB4, HOXB5, HOXB-AS3 (LOC404266) and MIR10A are located together on chromosome 17.

MIR10A is hypermethylated, HOXB5 and LOC404266 are hypomethylated in CD4⁺ T-cells from ME patients (1).

The HOXB4 gene promoter is hypomethylated in peripheral blood mononuclear cells (PBMC) from ME patients (table S7 in ref 2).

HOXB3 (5'UTR), HOXB4 (1stExon, 5'UTR), LOC404266, HOXB5 (5'UTR), LOC404266 (TSS200, TSS1500) and MIR10A (1stExon, TSS1500) are hypomethylated in PBMC from ME patients (table S4 in ref 2).

HOXB3 (5'UTR), HOXB4 (body), HOXB5 (3'UTR), LOC404266 (TSS200, TSS1500, body) and MIR10A (TSS1500) are hypermethylated in PBMC from ME patients (table S7 in ref 3).

HOXB3, HOXB4, LOC404266 and MIR10A are differentially methylated in ME subtypes (table S3 in ref 4).

Why are HOX-genes hypomethylated in Trivedi's study and hypermethylated in de Vega's study?

DNA methyltransferase DNMT3A and DNMT3B are responsible for de novo methylation, while DNMT1 is responsible for maintaining methylation signatures.

DNMT3A (TSS1500) is hypomethylated in the Trivedi study (table S4 in ref 2).

DNMT3A (body) and DNMT3B (5'UTR) are hypermethylated in the de Vega (2017) study (table S7 in ref 3).

DNMT3A (body) and DNMT3B (5'UTR) are differentially methylated in ME subtypes (table S3 in ref 4).

References:

1. Brenu et al: Methylation profile of CD4+ T cells in CFS/ME. J. Clin Cell Immunol 5, 228  
2. 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
3. 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/
4. 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-2017-0150