SPI1 and ME

SPI1 (=PU.1) is a transcription factor involved in hematopoiesis. SPI1 regulates B-cell development, but is also important for maturation of macrophages, T cell progenitors and T helper 9 cells.

SPI1 can either activate or repress the transcription of genes. This is mediated by the ability of SPI1 to build different complexes with a number of different protein partners (1).

In leukemia SPI1 can be either an oncogene or a tumor suppressor. SPI1 overexpression can trigger cellular senescence, and may be a safeguard against leukemia (12).

EP300 is a transcriptional co-activator, which interacts with SPI1. Epstein-Barr Virus nuclear antigen leader protein (EBNALP) coactivates EP300 and hereby dysregulates SPI1. An EP300 inhibitor can abolish EBNALP coactivation and may have the potential to control EBV-associated diseases (3).

SPI1 is a putative upstream regulator in adolescent CFS patients (table S4 in ref 4).

The gene SPI1 is hypermethylated (body, 5'UTR, 1stExon) in Me patients in one study (5), and hypomethylated (TSS200) in another study (6).

SPI1 interacts with several proteins where the genes are epigenetic changed. Fx, FLT3, CREBBP, E2F3, ELANE, HOXA10, GFI1, TFDP1 and IRF4 (5)

SPI1 also interacts with KAT2B (= EP300 / CBP associated factor). The gene promoter of KAT2B is hypomethylated in ME patients (6).

EP300 and CREBBP interacts with CITED2 (= CBP / p300 - interacting transactivator). CITED2 geneekspression is upregulated in ME patients (7, 8).

References:

1. Riel and Rosenbauer: Epigenetic control of hematopoiesis. Biol Chem 2014, 395, 11.
2. Delestré et al: Senescence is a Spi1-induces anti-proliferative mechanism in primary hematopoietic cells. Haematologica 2017, 102, 11.
3. Wang et al: Epstein-Barr Virus Nuclear Antigen Leader Protein Coactivates EP300. J Virol, 2018, 92, 9.
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.
5. de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11.
6. Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns. Plos One 2018, 13, 7.
7. Kerr et al: Gene expression subtypes in patients with CFS/ME. JID, 2008, 197.
8. Frampton et al: Assessment of a 44 gene classifier for the evaluation of CFS from PBMC gene expression. Plos one, 2011, 6, 3.