Thesis Title: IKK-dependent and independent signaling in inflammation and allergy
Supervisor: Prof. Vinay Tergaonkar
In the second part of this thesis, we mainly worked on mast cells and their epigenetic and transcriptomic responses in the context of immunoglobulin E (IgE) stimulation. Allergy is one of the least understood immunological responses partly due to the diversity of allergens and the complexity of immune response against them. In allergic responses, mast cells are key players with their ability to rapidly degranulate and also generate de novo lipids and transcripts. Although the molecular details of degranulation in mast cells were studied in allergic inflammation, the transcriptional response involving chromatin remodeling, enhancer dynamics and long non-coding RNA (lncRNA) expression is largely unexplored. Here, using mouse bone marrow derived mast cells (BMMCs), we characterized the steady state, IgE, and antigen (Ag) mediated epigenetic changes in mast cell chromatin and described the enhancer, super-enhancer, mRNA and lncRNA catalogue in these cells. Collectively, our findings provide insights into the mechanisms of the resolution of allergic inflammation, tissue remodeling and mast cell survival in allergic diseases.
ELKS is a ubiquitously expressed protein with pleiotropic functions in different cell types. Apart from its proposed role in pre-synaptic neurotransmitter release in neurons, ELKS was suggested to be an important regulator of tumor necrosis factor alpha (TNFα) mediated nuclear factor kappa light chain enhancer of activated B cells (NFκB) signaling in human cancer cell lines, by acting as a regulatory subunit of the IκB kinase (IKK) complex. However, genetic proof(s) for the involvement of ELKS in various functions of NFκB pathway were largely missing because of the embryonic lethality of ELKS knockout (KO) mice. In the first part of this thesis, to study the roles of ELKS in vivo, we generated 3 different ELKS conditional KO mouse models using Albumin-Cre (Alb-Cre), Lysozyme-Cre (LysM-Cre) and Vav-Cre models. Surprisingly, ELKS was found to be dispensable for many inflammatory actions in immune cells and hepatocytes. However, ELKS was found to be important for mast cell degranulation similar to its proposed role in neurotransmitter release in pre-synaptic neurons.
A) Allergen-induced transcriptomic changes in mouse bone marrow derived mast cells (BMMCs).
B) MMUG029490 is a novel lncRNA biomarker of allergic inflammation
For more information on Vinay TERGAONKAR’s laboratory, please click here.