Institut de Génétique Moléculaire de Montpellier (IGMM) - Montpellier, France
Transcription and Epigenomics in developing T-cells
Our laboratory focuses on understanding the genetic and epigenetic events that contribute to the phenotypes of cancer cells. We are particularly interested in understanding the molecular features that define the identity of tumor cells and how cellular transformation might be reversed as a therapeutic strategy. While much is known about the irreversible genetic changes involved in cancer initiation and progression, there is increasing interest in the reversible epigenetic modifications associated with tumorigenesis. To address issues of phenotypic plasticity in transformed cells, we study a lymphoproliferative disease induced by the intracellular protozoan parasite, Theileria. Theileria is the only eukaryotic parasite known to induce a cancer phenotype; namely, uncontrolled host cell proliferation, immortalization and invasion. In contrast to most transformation processes, which involve permanent mutations, this tumor phenotype is halted by treatment with the theilericidal drug, Buparvaquone, which kills the parasite and blocks cell proliferation and metastasis. Theileria transformation thus offers a unique system to study signaling and epigenetic mechanisms underlying tumor cell phenotypes.
Our laboratory is interested by the epigenetic and transcriptional events involved in the outcome of T-cell differentiation, using mouse as a model organism. How a stem cell becomes a fully differentiated T-lymphocyte represents a paradigm that can now be envisioned at the epigenetic level and genomic scale. Using ChIPseq and RNAseq, we recently showed that active enhancers associated to differentiation in thymic cells are transcribed and can be followed by the co-occurrence of specific epigenetic marks. We are now extending these genome-wide analyses to other differentiation stages and wish to understand how the dynamic of regulatory elements usage affects T-cell fate in normal and pathological states such as in type 2 diabetes and T-ALL cancer situations. The role of noncoding RNAs in mouse and human differentiation is also part of our interest, as we could show that enhancers can be transcribed with ou without polyadenylation of associated RNAs. We therefore developed several RNAseq protocol dedicated to the analysis of specific RNA populations (polyA-, total- and short-RNAseq).
Another aspect of our research project relies on deciphering the rules governing promoter and enhancer nucleosome positioning and depletion. We previously showed that CpG islands intrinsically deplete nucleosome at promoters, independently of transcription. We are now further investigating the structural determinants of nucleosome positioning and the influence of transcription both at promoters and enhancers.
Finally we are also investigating the role of novel post-translational modifications of the carboxy-terminal domain of Pol II. Based on biochemical and mutational approaches combined to genome-wide analyses, the precise role of these modifications in the transcription cycle will be investigated.
- Jean-Christophe Andrau, DR2 CNRS
- Ahmad Maqbool, Post-Doc
- Nicolas Descostes, PhD student
- Yousra Yahia, PhD student