Functional genomics of nuclear receptors
|Video: presentation of research topics developped by the team of J. Samarut|
Thyroid hormone receptors: how do they regulate metabolism in adults and their potential involvement in the development of metabolic diseases?
In Vertebrates Thyroid hormone (TH) has many different functions during development but also throughout adult life. It works by binding to its nuclear receptors TR which are transcription factors regulated by the availability of their ligand TH. In mammals two genes THRA and THRB respectively encode the two receptors TRa and TRb. Our group has a long lasting interest in dissecting the respective biological functions of these two receptors in mouse. To this end we have generated a large library of mice harboring mutations in the genes encoding the receptors. The characterization of these mice allowed us to show that TRa and TRb mainly fulfill different functions even though they can compensate for each other in some specific cases, such as body temperature control. In the past we have studied in details TRa during development and in particular its central role for the maturation of many organs such as central nervous system, intestine, heart or bone. More recently we shifted thematic to focus on TR functions in the adult. We currently study how they are involved in the regulation of many aspects of lipid and glucose homeostasis in the principal metabolic organs: liver, white fat and pancreas. Moreover we look at the potential impact of TR mutations and or TH deregulation on the development of diseases. We recently showed that TRa knock out was associated to accelerated atherosclerosis in mice harboring and ApoE knock-out background. Molecular investigations of this phenomenon lead to identify the development of inflammation processes consecutive to the absence of TRa.
We are now dissecting the molecular pathways through which TRa might control inflammation. These findings open new perspectives for understanding the genetic and molecular basis of atherosclerosis.
Androgen receptor: how does it control prostate tumor development?
Androgen receptor (AR) is a ligand-dependent transcription factor. Upon activating by androgens, AR regulates gene transcription through binding to specific regulatory regions of target genes. In men, AR is essential for both sexual differentiation and prostate development. It is implicated in every steps of the prostate cancer, which is the most common cancer among men in Western countries. Androgens activate cell proliferation at the very early stages of tumor development. At some advanced stage of tumor progression leading to metastasis, androgen suppression therapy becomes inefficient and tumor development becomes independent of androgens. Escape of tumor growth from the control by androgens results from alterations in the function of the androgen receptor-signaling pathway. The molecular bases of these alterations are still poorly understood. In any case identifying downstream target genes of AR should help in understanding the mechanisms through which AR signaling might activate prostate tumor cell proliferation. In addition, it is likely that identifying some of these genes might provide helpful diagnostic and prognostic markers of prostate tumor development.We have identified several new AR target genes, among which some genes producing microRNA. We also identified a new way of regulation of some target genes by cooperative action of AR and the transcription factor E2F1 through chromatin looping in the regulatory region of these genes.
Our aim is now to check whether some of these target genes might be prognostic markers for prostate tumor development. The molecular determinants of the functional interaction between E2F1 and AR are also investigated to open potential new ways of therapeutical approach.