Research
Metabolism-epigenetic interactions in Drosophila : P.Jouandin

We aim to understand the epigenetic and metabolic network controlling glycan-mediated immune recognition using a paradigm of autoimmunity in Drosophila adipose cells. Our multidisciplinary project combines metabolomics, functional genomics, and glycoproteomics. We use both targeted and systematic genetic approaches to study adipokines' role in the differentiation of immune effectors, and the role of glycan barcodes in recruiting these cells to adipose tissues. We interrogate the metabolic landscape regulating glycosylation during immune recognition, the transcriptional control of this process by chromatin remodelers, and how this affects the signals mediating adipose-immune cells communication. Deregulation of these processes altogether is a hallmark of cancers, and by investigating the fundamental mechanisms at play, we aim to provide insights into immune recognition regulation, aiding cancer and autoimmune disease therapies.

Axis 1 : Metabolic landscape regulating glycosylation in the context of immune recognition

The metabolic control of glycosylation is believed to occur mainly in terminal steps like hexosamine biosynthesis and glycosyltransferase activity. However, it also involves the synthesis of complex dolichol lipids, a process often overlooked but with significant pathological implications. Global orchestration of glycosylation by metabolic pathways is not well understood, nor how specific metabolic pathways support distinct functions in different cell types. We aim to characterize the global metabolic program regulating glycosylation in adipose cells in the context of immune recognition. We use isotope labelling and high-resolution mass spectrometry to identify the primary substrates used by this tissue and explore the connections between pathways, to study a "glycosylation superpathway" we identified, including the upstream control of glycan building blocks, glycan precursors, and dolichols.

Axis 2 : Chromatin remodelers and transcriptional control of the metabolic program of glycosylation mediating immune-tolerance

Chromatin remodelers, key components of the epigenetic machinery, regulate gene expression, DNA replication, repair, and recombination. Their mechanisms include nucleosome sliding, ejection, histone variant exchange, and posttranslational modification. However, their role in coordinating metabolic programs remains unclear. We analyze how chromatin remodeling complexes regulate self-tolerance in adipose tissue by controlling the metabolic program of glycosylation transcriptionally. We aim to identify their direct transcriptional targets affecting metabolic enzyme expression, and the signaling pathways they regulate.

Axis 3: Adipose tissue - immune cells communication

We implicated metabolism and chromatin remodeling defects in altered glycan assembly, glycoprotein abundance, and protein secretion. We study how this impacts adipokine secretion, immune differentiation and glycan barcodes in glycoproteins. We also explore how immune receptors integrate these signals into the control of for immune recognition and autoimmunity, aiming to understand glycosylation's roles during adipose tissue - immune cells communication, and the consequences its deregulation.