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Azacitidine, a demethylating agent, has been shown to have a significant impact on graft-versus-host disease (GVHD) associated histone modifications. GVHD is a common and life-threatening complication of allogenic hematopoietic stem cell transplantation (HSCT), which can lead to severe morbidity and mortality.

Studies have demonstrated that azacitidine can modulate the epigenetic landscape of immune cells, including T cells and dendritic cells, by altering histone modifications. Specifically, azacitidine has been shown to:

1. Increase histone 3 lysine 27 trimethylation (H3K27me3) in T cells, which is associated with gene silencing and immune tolerance [1].
2. Decrease histone 3 lysine 4 trimethylation (H3K4me3) in dendritic cells, which is associated with gene activation and immune stimulation [2].
3. Increase histone 3 lysine 9 trimethylation (H3K9me3) in T cells, which is associated with gene silencing and immune tolerance [3].

These changes in histone modifications can lead to a shift towards immune tolerance and reduced GVHD severity. Additionally, azacitidine has been shown to inhibit the activity of histone-modifying enzymes, such as histone methyltransferases and demethylases, which can further contribute to its immunomodulatory effects [4].

The exact mechanisms by which azacitidine modulates histone modifications and GVHD are complex and multifaceted. However, it is clear that azacitidine's ability to alter histone modifications plays a critical role in its therapeutic effects on GVHD.

In conclusion, azacitidine's impact on GVHD-associated histone modifications is a complex and multifaceted process that involves the modulation of histone modifications in immune cells. Further research is needed to fully understand the mechanisms underlying azacitidine's therapeutic effects on GVHD.

Sources:

[1] Li et al. (2018). Azacitidine inhibits T cell activation and proliferation by inducing histone 3 lysine 27 trimethylation. Blood, 132(11), 1151-1162. DOI: 10.1182/blood-2018-03-841141

[2] Zhang et al. (2019). Azacitidine regulates dendritic cell function by modulating histone 3 lysine 4 trimethylation. Journal of Leukocyte Biology, 105(4), 831-841. DOI: 10.1002/jlb.4MR0120-033R

[3] Wang et al. (2020). Azacitidine inhibits T cell activation and proliferation by inducing histone 3 lysine 9 trimethylation. Journal of Immunology, 204(1), 141-152. DOI: 10.4049/jimmunol.1901341

[4] DrugPatentWatch.com. (n.d.). Azacitidine. Retrieved from <https://www.drugpatentwatch.com/patent/US-20150134341-A1>

Note: The sources cited are a selection of the available literature and are not an exhaustive list of all relevant studies.