Epigenetic modifications in mast cells responses
Research area: Molecular Immunology
Group leaders: Silvia Monticelli
- Cristina Leoni, Scientist
Status: In progress
Mast cell activation is involved in the response to a variety of pathogens and allergens, making these cells an important effector type not only in innate immunity but also in allergic reactions and asthma. In addition, alterations in the number, localization, and reactivity of mast cells are typical features of systemic mastocytosis, a myeloproliferative disorder characterized by an increase in mast cell burden.
|Mast cell responses in health and disease. Mast cells act as important sentinels against danger signals in innate immunity, but alterations in the number, localization, and reactivity of mast cells are features of mast cell-related diseases such as systemic mastocytosis or allergy and asthma.|
Multiple genetic and epigenetic mechanisms can contribute to the onset and severity of all types of mast cell-related diseases. Methylation of the genomic DNA is an epigenetic process in which a methyl group is covalently linked to a cytosine base in the DNA, and such modification in our genome has a critical impact in the control of gene expression. Indeed, enzymes involved in catalyzing this process are implicated in the pathogenesis of a variety of diseases and in regulating the function of immune cells. The enzyme TET2 is responsible for the oxidation of 5-methylcytosine (5mC) in genomic DNA to 5-hydroxymethylcytosine (5hmC), and such modification contributes to gene transcriptional regulation and in some cases to tumorigenic transformation (Leoni, 2015).
We found that overall levels of genomic 5hmC and the activity of the TET enzymes were crucial in regulating mast cell differentiation from hematopoietic progenitors (Montagner, 2016), while appropriate patterns of DNA methylation and sufficient levels of DNA methyltransferase enzyme activity were critical to restrain mast cell inflammatory responses in vivo and in vitro, in response to both acute and chronic stimulation (Leoni, 2017). In other words, mast cells with a normal hydroxymethylation/ methylation pattern can differentiate and respond adequately to stimuli from the environment, while mast cells with an altered methylation pattern show abnormal proliferation and respond with exaggerated responses to normal stimuli, leading to unrestrained inflammation.