Anatomical Profiling of Nuclear Receptor Expression Reveals a Hierarchical Transcriptional Network

Abstract

In multicellular organisms, the ability to regulate reproduction, development, and nutrient utilization coincided with the evolution of nuclear receptors (NRs), transcription factors that utilize lipophilic ligands to mediate their function. Studying the expression profile of NRs offers a simple, powerful way to obtain highly relational information about their physiologic functions as individual proteins and as a superfamily. We surveyed the expression of all 49 mouse NR mRNAs in 39 tissues, representing diverse anatomical systems. The resulting data set uncovers several NR clades whose patterns of expression indicate their ability to coordinate the transcriptional programs necessary to affect distinct physiologic pathways. Remarkably, this regulatory network divides along the following two physiologic paradigms: (1) reproduction, development, and growth and (2) nutrient uptake, metabolism, and excretion. These data reveal a hierarchical transcriptional circuitry that extends beyond individual tissues to form a meganetwork governing physiology on an organismal scale.

Nuclear receptors, mitochondria and lipid metabolism

“…To date, 48 and 49 members of the NR superfamily have been identified in humans and mice, respectively (Mangelsdorf et al 1995;Bookout et al 2006). The first receptors to be cloned, the endocrine nuclear hormone receptors, were discovered in an effort to define the mechanism of action of known hormones, such as: the amino-acid-derived thyroid hormone; the steroidal glucocorticoid, mineralocorticoid, and sex hormones; and the vitamins A and D. Several of these endocrine receptors, e.g.…”

“…Expression of PPAR is greatest in tissues with active metabolism, such as BAT, liver, striated muscle, and kidney (Bookout et al 2006). PPAR has a very broad expression pattern that made identifying its role more difficult.…”

“…Expression of LXR is greatest in fat, liver and macrophage Bookout et al 2006). In contrast, LXR is widely expressed.…”

“…There are three isoforms of RXR: RXRα, RXRβ, and RXRγ (Bookout et al 2006). RXRα is broadly expressed with highest expression in the liver.…”

Non-coplanar polychlorinated biphenyls (PCBs) are direct agonists for the human pregnane-X receptor and constitutive androstane receptor, and activate target gene expression in a tissue-specific manner

“…Given the diverse functions that nuclear receptors undertake within the body in general (Bookout et al, 2006), and the liver specifically (Plant and Aouabdi, 2009), it is likely that agonism of PXR and/or CAR by non-coplanar PCBs may have impacts on these systems. In particular, nuclear receptors are associated with the regulation of metabolic homeostasis, through both the action of endosensing receptors such as LXR, FXR and PPAR (Barbier et al, 2002;Mohan and Heyman, 2003), and xenosensing receptors such as PXR and CAR (Bachmann et al, 2004;Pascussi et al, 2008;Wada et al, 2009).…”