Team 7: (P. Brousset): to understand the role of RNA biology in hematopoietic cancers
In the last decade, it has become increasingly clear that post-transcriptional control of gene expression plays an essential role in tumor cell dysregulation. Studies at the RNA level in cancer have been focused for a long time on mRNA, the best known RNA family that represents only a small part of transcripts (2 to 5% of total RNAs). However, the human genome contains much more than just protein-coding genes and that the majority of transcribed RNAs are non-coding (ncRNA), such as microRNAs (miRNA), long non-coding RNAs (lncRNA), interfering RNAs, piwiRNAs, and small nucleolar RNAs (snoRNA). Evidence is accumulating that these ncRNAs play key roles in regulating numerous pathways involved in cancer development and progression. As microRNAs are deeply involved in modulation of proliferation, apoptosis and cell differentiation, their role in hematopoietic malignancies are currently largely studied. Despite these intensive researches, the functions of lncARNs and snoARNs in the canonical pathways of carcinogenesis are not yet wellknown, or even unknown. One of the main challenges in understanding the function of a specific non-coding RNA in cancer is deciphering its interactome (other RNAs, specific protein complexes, regions of DNA…). Several new technologies have emerged and allow now addressing this gap.
The lab explores the expression profiles and functions of microRNAs, snoRNAs and lncRNAs in hematological malignancies but also the interaction between ncRNA and proteins. Three types of tumors for which our team has an international expertise or represent cancers with potential of resistance are investigated: T-cell lymphoma including anaplastic large cell lymphoma, B-cell chronic lymphocytic leukemia and acute myeloid leukemia.
Our objectives are:
- to decipher how ncRNAs dysregulation in leukemias/lymphomas could impact on their prognosis (relapse, response and resistance to treatment) and ideally to identify prognostic biomarkers.
- to study :
- the physiological and pathological role of these ncRNA including the identification of their downstream target genes, whose role in classical (proliferation, survival, invasion) and new (autophagy, ER stress) pathways of cancerogenesis will be functionally characterized.
- the upstream mechanisms of ncRNA regulation (epigenetic control of their expression,control of their stability by RNA-BP or specific endoribonucleases).
Ours projects are based first on transcriptomic profiling studies with commercial chips, «RNAseq» and «small RNA-seq». Regulation mechanisms of the ncRNA identified in the previous step, more particularly epigenetic control of their expression, control of their maturation and stability through ribonucleoproteic complexes are studied using ChIP (chromatin Immunoprecipitation), RIP (RNA Immunoprecipitation), biotin pull-down and/or PARCLIP (Photoactivatable Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation).
Pierre Brousset's team is part of Labex TOUCAN