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Anatomical Profiling of Nuclear Receptor Expression Reveals A Resource Anatomical Profiling of Nuclear Receptor Expression Reveals a Hierarchical Transcriptional Network Angie L. Bookout,1 Yangsik Jeong,1 Michael Downes,2 Ruth T. Yu,2 Ronald M. Evans,2 and David J. Mangelsdorf1,* 1 Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA 2 Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA *Contact: [email protected] DOI 10.1016/j.cell.2006.06.049 SUMMARY fat-soluble vitamins A and D, thyroid hormone, fatty acids, oxysterols, bile acids, and numerous xenobiotic lipids de- In multicellular organisms, the ability to regulate rived from the diet. Additional members of this family are reproduction, development, and nutrient utili- called orphan receptors because their ligands remain zation coincided with the evolution of nuclear unknown. Together, NRs govern expression of genes in- receptors (NRs), transcription factors that uti- volved in a broad range of reproductive, developmental, lize lipophilic ligands to mediate their function. metabolic, and immune response programs. NRs also Studying the expression profile of NRs offers a encompass one of the most successful targets for drugs currently available or being developed to treat a multitude simple, powerful way to obtain highly relational of therapeutic indices, including hypertension, cancer, di- information about their physiologic functions as abetes, cardiovascular disease, cholesterol gallstone dis- individual proteins and as a superfamily. We ease, and the metabolic syndrome (Gronemeyer et al., surveyed the expression of all 49 mouse NR 2004; Shulman and Mangelsdorf, 2005). mRNAs in 39 tissues, representing diverse ana- Although much has been learned about the physiology tomical systems. The resulting data set un- of certain receptors in a limited number of well-studied tar- covers several NR clades whose patterns of get tissues, surprisingly little is known about NR function in expression indicate their ability to coordinate the majority of tissues throughout the body as a whole. the transcriptional programs necessary to af- Furthermore, relatively little is known about the complexity fect distinct physiologic pathways. Remark- of interactions that may exist between receptors in various ably, this regulatory network divides along the tissues and, consequently, about whether such interac- tions may direct a higher order process to govern dynamic following two physiologic paradigms: (1) repro- physiological parameters. Indeed, the ability of NRs to duction, development, and growth and (2) nutri- crossreact with each other’s DNA binding sites and to ent uptake, metabolism, and excretion. These govern similar regulatory cascades implies the existence data reveal a hierarchical transcriptional cir- of such a higher-order transcriptional regulatory network. cuitry that extends beyond individual tissues This raises the question of whether understanding this to form a meganetwork governing physiology network can be obtained not only by studying the expres- on an organismal scale. sion of individual receptors but also by studying expres- sion of the nuclear receptor superfamily as a whole using a systems biology approach. One simple but elegant way INTRODUCTION to define the blueprint of NR action on a system-wide scale is to look at the expression of the entire NR tran- Nuclear receptors (NRs) represent the largest family of scriptome. Given that physiology is a process occurring transcription factors found in metazoans (Mangelsdorf across both spatial and temporal coordinates, this ex- et al., 1995). The success of members of this group stems pression blueprint would be expected to have both an an- in part from their ability to function as ligand-dependent atomical and circadian rhythm component. sensors for a diverse set of fat-soluble hormones, vita- The Nuclear Receptor Signaling Atlas (NURSA; www. mins, and dietary lipids (Chawla et al., 2001). Included in nursa.org) is an interdisciplinary consortium focused on this family are receptors for endocrine steroids (i.e., corti- creating a web-based, minable, dynamic database of nu- costeroids, progesterone, androgens, and estrogens), clear receptor and coregulator sequence information, Cell 126, 789–799, August 25, 2006 ª2006 Elsevier Inc. 789 expression analysis, and functional data. NURSA aims to congenita on the X chromosome, gene 1 (DAX-1); estrogen provide tools that may catalyze progress in a number of in- receptor b (ERb); farnesoid X receptor b (FXRb); hepato- terdisciplinary fields. Therefore, as members of the group, cyte nuclear factor 4a (HNF4a); liver receptor homolog-1 we first set out to establish the anatomical expression (LRH-1); photoreceptor-cell nuclear receptor (PNR); preg- profiles for the 49 members of the NR superfamily in 39 nane X receptor (PXR); short heterodimer partner (SHP); tissues from two different strains of the most widely steroidogenic factor 1 (SF1); and tailless homolog orphan used mouse models. In a companion paper in this issue receptor (TLX). Within this restricted set the CNS, endo- of Cell, Yang et al. (2006) describe the circadian expres- crine, and enterohepatic tissue systems were represented, sion of NRs in four metabolically relevant tissues. The re- highlighting the specialized function of these receptors as sulting data sets offer an unprecedented view of NR func- tissue-specific transcription factors. tion in space and time. The work presented here suggests When grouped according to tissue system (e.g., CNS, that hierarchical, integrated NR networks coordinately re- endocrine, gastroenteric, metabolic, immune, reproduc- lay cues directing tissue-specific and metabolic readouts. tive, cardiovascular, and structural), the distribution and This resource should provide new avenues for more ad- level of expression of individual NRs becomes apparent vanced investigation into the biological role of each recep- (Figure 1B). Receptors that were expressed in most tis- tor individually and together as a superfamily. sues at moderate to high levels (i.e., relative mRNA values R 0.1 arbitrary units) included the chicken ovalbumin up- RESULTS AND DISCUSSION stream promoter-transcription factor g (COUP-TFg), es- trogen-related receptor a,(ERRa), glucocorticoid receptor Anatomical Expression Profiling of the NR (GR), liver X receptor b (LXRb), and retinoid X receptors Superfamily a and b (RXRa, RXRb). Interestingly, LXRb and RXRb ex- TaqMan-based real-time quantitative RT-PCR (QPCR) hibited the highest level of NR expression found in all was chosen to survey NR expression because of its broad mouse tissues (i.e., relative mRNA value of 1.0 or higher). dynamic range of detection, quantitative reliability and Several other receptors (e.g., PNR, HNF4a and g, and reproducibility, and high-throughput capacity. Transcript SF1) maintained relatively high levels of expression (rela- levels of the major isoforms of the 49 known mouse NRs tive mRNA value R 2.0), but only in a few tissues. It is were profiled in 39 different tissues from two strains of worth noting that these profiles represent a fixed point in mice, 12931/SvJ and C57/Bl6. Male mice were used for time (ZT 0) and that expression of many receptors is mark- all tissues except female reproductive tissues, reflecting edly influenced by circadian expression as evidenced in the common use of male mice in most experimental sys- the companion paper by Yang et al. (2006). In addition, be- tems. The two mouse strains were chosen because of cause of the heterogeneous population of cells in some their wide use in genetic manipulation and their metaboli- tissues, it is more difficult to interpret low levels of expres- cally diverse phenotypes. For example, 12931/SvJ mice sion exhibited by receptors in certain organs or tissue are relatively resistant to lipid-related disorders in spite samples. For example, TLX expression, which is limited of high plasma triglycerides and cholesterol levels, while to the brain, was detected by QPCR in whole brain sec- C57/Bl6 mice are susceptible to diet-induced obesity, ath- tions at low levels. However, when analyzed at the level erosclerosis, and type II diabetes (MGD, 2003). The ana- of individual cells, TLX expression is known to be highly tomical profile of all 49 NRs in the two strains of mice is expressed, but only in a subset of adult neural stem cells depicted on Poster S1, and the entire data set is available (Shi et al., 2004). on the NURSA website at <www.nursa.org/datasets. cfm?doi=10.1621/datasets.02001>. Analysis of these Hierarchical Clustering of NR Expression: The data revealed nearly complete identity in the expression Reproductive and CNS Axes profile of NRs between the two mouse strains, although To study the potential relationship between receptor ex- 12% of the tissues exhibited differences greater than pression, function, and physiology, the QPCR results 2-fold between strains (see accompanying poster). At an were analyzed by hierarchical, unsupervised clustering of organismal level, the tissue-frequency profile showed receptor expression by tissue (Figure 2). The resulting den- that 21 NRs were expressed in all tissues, 17 NRs existed drogram on the receptor axis reveals the existence of in more than half but not all tissues, and 11 NRs were re- a higher-order network tying nuclear receptor function to stricted to less than 50% of tissues in the adult animal physiology. Unexpectedly
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