BET bromodomains epigenetic signaling in normal bone biology – EPIBONE
Bone pathologies exhibit diverse and often combined genetic, hormonal, inflammatory and environmental origins. These pathologies (osteopetrosis, osteolysis expensive, Paget ‘s disease, osteoporosis, rheumatoid arthritis, bone cancer metastasis...), affecting altogether millions peoples around the world, correspond to local or generalized imbalance of the differentiation/function of cells in charge of bone apposition (osteoblasts) and bone resorption (osteoclasts). Therefore, the identification of new mechanisms and new therapeutic targets constitute a major clinical challenge to improve patients’ care and to ameliorate their clinical outcome.
Bone remodeling is controlled by a very complex extracellular network, mainly composed by numerous cytokines controlling osteoblastic differentiation as well as osteoclastic bone resorption. One major factor appears as a key molecules orchestrating the osteoclast differentiation process and survival: the Receptor Activator of NF-kB Ligand (RANKL) which is dedicated to the osteoclast fusion, activation and survival. RANK/RANKL signaling is associated with the activation of specific transcription factors like NFATc1 whose expression is required to sustain osteoclastogenesis. All these data reveal the therapeutic interest of the RANKL axis modulation.
Histone modifications are of critical importance for the maintenance of the transcription program of normal cells. The bromodomain and extra-terminal domain (BET) protein family is an important class of “epigenetic reader proteins” which function to recognize the N-acetylation of lysine residues on histone tails. Bromodomain-containing proteins act as a scaffold for molecular complexes at recognized histones sites in order to regulate chromatin accessibility to transcription factors and RNA polymerase.
Interestingly, recent studies have identified an asymmetric distribution of BRD4 (BET protein) at enhancer regions across the epigenome, the so-called super-enhancers. These super-enhancers are associated with key cell type specific genes known to play prominent roles in the biology of normal cells, Thus, JQ1, a pharmacologic BET inhibitor, was shown to reduce the transcription of such genes, whose expression is more sensitive to the presence of BET bromodomains.
The consequence of this pharmacologic inhibition of bromodomains is selective gene expression alteration, mediated by selective disruption of strong enhancer-mediated transcription at essential cell specific transcription factors loci. Those super enhancers (highly enriched for BET proteins) are present differentially depending on the cell type in order to activate specific transcriptional program for each cell type and context.
To date, no study has ever investigated the super-enhancer organization in bone biology. We propose to elucidate the potential roles and organization of the BET bromodomain protein (and to localized super-enhancers) in the bone remodeling process in order to identify new therapeutic targets in pathologies linked to osteolytic disorders. We plan to use JQ1 (inhibitor of BRDs) as a chemical tool to investigate the regulation mechanisms both in vitro and in vivo.
The goal of this project is to evaluate the roles of BET bromodomains proteins epigenetic signaling in bone turnover, more specifically on osteoclastogenesis and osteoblastogenesis and on their relationship to their micro-environment.
We believe that studying in details the context dependent (presence or not of RANKL for example) distribution of the BETs proteins on the genome might lead to the identification of unknown genes and the BET-associated transcription factors regulating them, essential for bone physiology. Consequently we plan to identify new targets for the treatment of osteolytic disorders like osteoporosis and the development of new prognostic tools (in regard with the risk of osteolytic process).
Monsieur Benjamin ORY (Laboratoire de physiopathologie de la resorption osseuse, Université de Nantes)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
LPRO INSERM UMR 957 Laboratoire de physiopathologie de la resorption osseuse, Université de Nantes
Help of the ANR 272,799 euros
Beginning and duration of the scientific project: September 2016 - 36 Months