H3 and H4 histones have long tails. The tail can be modified in different ways, that lead to activation or repression of transcription of genes. Fx, trimethylation of H3 lysine 4 (H3K4me3) will acrivate transcription, and trimethylation of H3 lysine 27 (H3K27me3) will repress genes.
COMPASS (complex of proteins associated with Set1) - like complexes activate transcription. They perform the histone modification H3K4me3.
Polycomb complexes repress genes. The polycomb repressive complex 2 perform the histone modification H3K27me3.
Several subunits of COMPASS are shared with the super elongation complex (SEC).
The balance between COMPASS/SEC mediated transcription and polycomb mediated repression of transcription, regulate many genes - particularly HOX gens.
MLL is a H3K4 methyltransferase and is part of SEC/COMPASS - like complexes. MLLT1 is a SEC subunit. ASXL1 is a member of the polycomb group.
MLL and ASXL1 interact with HOXA9, which is involved in hematopoiesis.
HOXA9 interacts with MEIS1, PBX2 and TRIP6.
HOXA9 regulates FLT3, MYB and LMO2.
HOXA9 is a putative upstream regulator in adolescent CFS-patients (table S4 in ref 1).
Epigenetic changed genes in ME patients:
- MLL, hypermethylated 3'UTR
- MLLT1, hypermethylated body, q
- ASXL1, hypomethylated body, q
- HOXA9, hypermethylated body, q, s
- MEIS1, hypermethylated body, q, s
- PBX2, hypermethylated body, hypomethylated TSS1500, q, s
- TRIP6, hypermethylated body, TSS1500, q,
- FLT3, hypermethylated body, q
- MYB, hypermethylated body, q, s
- LMO2, hypermethylated 5'UTR, TSS1500, 1st Exon, q, s
s = the gene is differentially methylated in subtypes of ME patients (3).
String interaction network - HOXA9 from www.genecards.org
This is just the tip of the iceberg. Several COMPASS/SEC, polycomb proteins and HOX genes are involved in the ME pathomechanism. And they relate to the dysregulated metabolism.
- 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
- de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11
- de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5