HOXA9 and ME

Histones act as spools around which DNA winds.

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

q = the methylation is related to quality of life in ME patients (2).
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.

References:

1. 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
2. de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11
3. de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5

Nucleoporins in ME

The nuclear pore complex (NPC) mediates nuclear transport of RNA. Nucleoporins are the main components of the NPC. Certain nucleoporins have additional function in chromatin organization and transcription regulation.

NUP98 and NUP96
The gene NUP98 encodes nucleoporin Nup98 and Nup96. They are expressed from one mRNA. Following translation, autoprotelytic cleavage separates the two proteins. Alternatively, Nup98 can be spliced as a short mRNA that does not encode Nup96 (1).

Interferon-induced gene promoters containing Nup98 accumulate poised RNA Pol II along with dimethylated histone H3K4 (1).

NUP98 recruits the Wdr82-Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells (2).

Nup98 associates with Trx/MLL and NSL Histone-modifying complexes and regulates Hox Gene expression (3).

Mice with low levels of Nup96 have impared interferon mediated induction of MHCI and II and altered T- and B-cell function (4).

NUP98 and HOXA1 are involved in the ME pathomechanism in severely ill ME patients (5).

Depletion of FOXK1 attenuates virus-inducible interferon-stimulated response element (ISRE) reporter expression. Drosophila FOXK interact with Nup98 to regulate antiviral gene expression (6).

FOXK1 is hypermethylated in ME patients in two studies (7, 8). The hypermethylation (3'UTR and body) is related to quality of life in ME patients (table S7 in ref 8).

FOXK1(body) is differentially methylated in ME subtypes (no 673 in table S3 in ref 9).

References

1. Franks et Hetzer: The role of Nup98 in transcription regulation in healty and diseased cells. Trends Cell Biol. 2013, 23, 3
2. Franks et al: Nup98 recruits the Wdr82-Set1a/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells. Genes Dev. 2017, 15, 31
3. Pascual-Garcia et al: Nucleporin Nup98 associates with Trx/MLL and NSL histone-modifying complexes and regulates HOX gene expression. Cell Rep. 2014, 9
4. Favia et al: The nucleoporin Nup96 is required for proper expression of interferon-regulated proteins and functions. Immunity 2006, 24
5. Pihur et al: Metaanalysis of CFS through integration of clinical, gene expression, SNP and proteomic data. Bioinformation 2011, 6, 3
6. Panda et al: The transcription factor FOXK participates with Nup98 to regulate antiviral gene expression. MBio, 2015, 7, 2
7. de Vega et al: DNA methylation Modifications associated with CFS. PlosOne, 2014, 9, 8
8. de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11
9. de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5

mRNA export in ME

DNA is transcribed into pre-mRNAs.

mRNAs are packaged into pre-messenger ribonucleoproteins (pre-mRNPs).

Pre-mRNPs are spliced into mature mRNPs.

mRNPs are exported out of the nucleus through the nuclear pore complex (NPC).

SUN1 (=UNC84) is a nuclear envelope protein.

SYNE proteins (nesprins) are part of a network that connects the nuclear envelope to the cytoskeleton.

NXF1 is an export factor.

NUP153 is one of several nucleoporins.

SUN1 recruits NFX1-containing mRNPs onto the nuclear envelope and hands them over to NUP153 (1).





Figure from: Li and Noegel: Inner nuclear envelope protein SUN1 plays a prominent role in mammalian mRNA export. Nucleic Acids Research 2015, 43, 20, 9874-9888 (1).

The gene SUN1 is hypomethylated in CD4⁺  T cells (2), and in peripheral blood mononuclear cells (PBMC) from ME patients in two studies (3, 4).

The hypomethylation is related to quality of life in ME patients (table S7 in ref 4).

SYNE1 and SYNE2 are hypermethylated in ME patients (3, 4). The SYNE2 hypermethylation (body and TSS1500) is related to quality of life in ME patients (table S7 in ref 4).

SYNE2 is differentially methylated in ME subtypes (no 73 and no 1732 in table S3 in ref 5).

NXF1 is hypermethylated (TSS1500) in ME patients and the methylation is related to quality of life (table S7 in ref 4).

NXF1 gene expression is up-regulated (adjustet p-value = 0,0682) in whole blood from adolescent CFS patients (6).

References:

1. Li and Noegel: Inner nuclear envelope protein SUN1 plays a prominent role in mammalian mRNA export. Nucleic Acids Research 2015, 43, 20, 9874-9888 (1)
2. Brenu et al: Methylation Profile of CD4⁺  T cells in CFS/ME. J. Clin Cell Immunol 2014, 5, 3.
3. de Vega et al: DNA methylation Modifications associated with CFS. PlosOne, 2014, 9, 8
4. de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11
5. de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5.
6. Nguyen et al: Whole blood gene expression in adolescent CFS: an exploratory cross-sectional study suggesting altered B cell differentiation and survival. J Trans Med, 2017, 15, 102.