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Mol Endocrinol. Feb 2010; 24(2): 279–285.
Published online Oct 21, 2009. doi:  10.1210/me.2009-0276
PMCID: PMC2817609

Minireview: The SRC Family of Coactivators: An Entrée to Understanding a Subset of Polygenic Diseases?

Abstract

In this perspective, we present the idea that SRC family coactivators are likely agents in human polygenic disease states based upon a number of interlocking aspects of their biology. We argue that their role as key integrators of environmental signals and their ability to regulate the expression of myriad downstream genes makes them likely candidates for strong positive evolutionary selection pressures. Based on the fact that they work as part of multiprotein coactivator complexes, we predict that individual coactivator alleles exist as weakly penetrant disease alleles, each contributing only a fraction of transcriptional activity to the whole coactivator complex. In this way, individual coactivator alleles are free to evolve in the absence of strong negative selection. Emerging genomic and proteomic approaches promise to advance the characterization of coactivator proteins and their physiological functions, allowing us to have a greater appreciation of their roles as master regulators at the nexus between genetics, reproduction, metabolism, cancer, other human diseases, and our environment.

The three members of the steroid receptor coactivator (SRC) family, SRC-1 (1), SRC-2/TIF2/GRIP1 (2), and SRC-3/AIB1/RAC3/ACTR/pCIP/TRAM-1 (3,4,5,6,7) play central roles in reproduction, metabolism, immunity, and cancer (8,9). They function primarily to enhance the transcriptional activity of nuclear receptors (NRs) and other transcription factors, a role that is dynamically regulated by upstream signaling systems (10). These upstream systems write a combinatorially diverse posttranslational modification (PTM) code on coactivator proteins that control factor-specific coactivation of a variety of NRs and other transcription factors. As signal integrating hubs that are able to accept and retain complex information from our environment, SRC family coactivators act as key agents in transmitting this information into appropriate and coordinate gene expression programs.

Over the course of our evolution, human beings have endured dramatic changes in their environment, placing strong selection pressures on genes involved in responding to these abrupt changes in human existence. Our changing diet, longevity, and exposure to communicable diseases have created acute genetic challenges. The migrations of humans to distinctly different environments throughout the Earth (tropical, desert, arctic, temperate, etc.), the Neolithic advent of agriculture, the rapid transition to industrialization, and the dramatic increase in lifespan have all placed acute selective pressures on the human genome that were required for dynamic responses to the rapid changes in the environment (11). As an example of this phenomenon, the thrifty gene hypothesis predicts that although energy conservation was an important issue in our recent evolutionary past, today these same energy-conserving traits are responsible in part for the emergence of obesity and diabetes (12), although genetic drift should also be considered as well (13). More recent thinking on this issue highlights the important evolutionary relationship that exists between energy metabolism and reproduction (14,15). In particular, female reproductive capacity is carefully tuned to food and energy status (16). Experimental evidence linking SRC family coactivators to both energy metabolism and reproduction is particularly interesting, considering their role as integrators of hormone and growth factor signaling systems.

The relationship between genes and environment will be in flux when displaced from Hardy-Weinberg equilibrium; better suited alleles will concentrate in human populations in response to these new environmental forces (17). Consistent with this idea, evidence points to coactivator alleles being part of this process. Computational studies to identify alleles subject to strong selective pressure sweeps have identified a number of coactivators as agents of positive selection in different human populations (18,19). Of all human genes, SRC-1 (NCOA1) was found to be subject to the strongest selection pressure in the HapMap of genetic polymorphisms in the African population.

Monogenic and Polygenic Genetic Disorders

Because negative selection drives out deleterious alleles from populations, genetic diseases with monogenic etiologies are relatively rare. Inherited monogenic diseases are easier to understand and study and follow clear Mendelian rules and can be traced through family pedigrees (Fig. 1A1A).). On the other hand, the genetic basis of many common disorders such as obesity (20,21), diabetes (22), dyslipidemia (23), allergies (25), polycystic ovarian syndrome (24), hypertension (26), and central nervous system disorders (27) are primarily polygenic. Genome-wide association studies have had limited success in identifying the weakly penetrant alleles that underlie these diseases (28). Nevertheless, certain examples exist for SRC family members. A single-nucleotide polymorphism adjacent to SRC-1 has been identified as a significant and highly ranking risk factor for type 1 diabetes (29). In another study, a polymorphism in SRC-3 was found to contribute to the success of chemotherapy in the treatment of acute lymphoblastic lymphoma (30). Common individual polygenic disease-associated alleles have very low phenotypic penetrance, are not subject to strong negative selective pressure, and likewise are found at much higher frequencies in human populations. For a number of reasons that we will discuss below, including evidence from mouse knockout studies, SRC family coactivator genes have relatively low phenotypic penetrance, likely standing with other common but weakly penetrant alleles that contribute to polygenic disease states.

Figure 1
Models for monogenic, polygenic, and coactivator-based genetic disease. A, In monogenic diseases, the homozygous inheritance of two disease alleles for a single critical gene results in a rare but highly penetrant genetic syndrome. B, When inherited in ...

Coactivators as Master Regulators

The idea that master regulator proteins exist at the nexus between cellular pathways involved in cell cycle, cancer, metabolism, and external environmental stimuli has been posited for a number of proteins. One such example is p53, which integrates information about genome integrity and cell stress and makes appropriate decisions concerning cell fate in response to stress or DNA damage (31). In the same sense, SRC family coactivators function as key signal integrators, receiving information from upstream signaling pathways (10) such as growth factor activation of kinases that target SRCs. This information is transmitted as PTMs (e.g. phosphorylations) at distinct residues on the coactivator protein, which form a coactivator PTM code, controlling the coactivator's downstream function. SRCs then coactivate distinct transcription factors in a PTM-code-specific manner. The immense combinatorial complexity that can potentially be affected by PTMs on coactivator proteins allows these molecules to code for a very large number of states, effectively representing diverse and subtle stimuli from our environment (32).

Another important and somewhat counterintuitive characteristic of SRC family coactivators is the fact that even complete loss of these genes is not lethal. Interestingly, this also applies to other master regulators such as p53 (33) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) (34). We postulate that this is an important element that allows these proteins the flexibility to accommodate diverse signals from the environment. In contrast, genes that underlie core biological processes such as RNA polymerases or histones, for example, are likely to be intolerant of any change, unable to exist as weakly penetrant alleles in human populations, and ultimately unable to contribute to polygenic disease states.

PGC-1α: A Master Regulator of Energy Metabolism

In addition to SRC family coactivators, PGC-1α also stands out as a master regulator in the regulation of energy metabolism. PGC-1α was first characterized as a cold-inducible coactivator responsible for the regulation of adaptive thermogenesis (35). Subsequent work revealed its broad role in diverse aspects of energy metabolism (36). Like SRC family coactivators, PGC-1α function is subject to PTM-based coding by phosphorylation, methylation, and acetylation, which allow it to exist in distinct and diverse regulatory states. In contrast to most other coactivators, PGC-1α expression also is strongly regulated at a transcriptional level (35). Given the central role that PGC-1α has in meeting the strongly dynamic needs in regulating energy metabolism, it is apt to consider it as another master regulator, alongside SRC family coactivators.

Works Well with Others

Recent advancements in high-throughput proteomic technologies are allowing us a means to understand how multiple proteins work together at a functional level (37). After the discovery of NR coregulators, molecular biological analyses revealed that coactivators and corepressors, like other regulatory proteins, exist in large steady-state multiprotein complexes in mammalian cells (38,39). We now believe that gene transcription occurs as a consequence of the sequential recruitment by DNA-binding transcription factors of a series of different coactivator complexes that are required for accurate and efficient gene expression (40). Within these multisubunit complexes exist the many diverse enzymes that are needed to direct distinct subreactions of transcription such as histone acetylation, methylation, ubiquitination, nucleosome rearrangement, transcriptional initiation and elongation, RNA splicing, and finally, degradation of the activated coregulators and transcription factors themselves (9). In short, our current understanding of transcription is quite different from the earlier theories that gave great weight to the role of a single functional protein in this process. Many examples of the isolation of multiprotein complexes and their compositions now are available (NURSA.org), and the cooperative actions of different coactivators in the transcription of specific genes have been demonstrated repeatedly in cultured cells (5,41,42). Although we have limited information on this cooperative process in living animals and humans, logic dictates that it represents the norm in gene transcription in vivo as well.

Coactivators Provide Extensive Regulatory Finesse in the Complex Human Environment

Most animals make due with a roughly similar number of protein coding genes. Humans and mice possess about 20,000 genes, Caenorhabditis elegans about 19,000 genes, and Drosophila 13,000 genes (43,44,45). Despite this genetic limitation, humans possess an astoundingly more derived phenotype than these other species. The heightened degree of complexity in the human phenotype is likely due to increased regulatory control in the expression of this fixed number of genes. As discussed above, coactivators are prime sources of regulatory finesse due to the large number of PTM-coded states they can represent (32). Different combinations of phosphorylation, ubiquitination, acetylation, methylation, and SUMOylation on a single coactivator, like SRC-3, have the calculated potential to give rise to many billions of distinctly coded forms of the coactivators (32). Although this combinatorial potential is unlikely ever to be reached, the calculation clearly emphasizes the potential power of the human proteome.

Making Decisions by Committee

If one accepts this premise, then logic dictates that because multiple coactivator proteins exist in complexes, and that each have distinct functions subject to PTM coding, the final output of the complex is a composite of the environmental signals and the individual functions of each of the coactivator proteins. In this way, allelic differences in members of the coactivator protein complex can alter expression levels of many downstream genes. It then follows that the regulation of RNA polymerase II, gene transcription, and the genetic products will be highly pleiotropic. If the target gene is rate limiting in terms of a transcription pathway, one would expect that defects in almost any of the requisite proteins contained in a coactivator complex would affect its final output function in some manner. Although it is unlikely that each protein in the complex would have an identical quantitative function, they certainly would be likely to act as genetic modifiers of target gene responses under conditions when a signaling pathway is activated or when a cell is stressed.

An added feature to this distributed pleiotropic control of transcription is that it allows mixing and matching of weakly penetrant coactivator alleles. Because of the distributed and fractional roles played by individual coactivators in their complexes, coactivators are thus free to evolve in human populations as discussed above. Indeed, genetic disruption of SRC-1 (46), SRC-2 (47), or SRC-3 (48,49) is not lethal in mice, although their disruptions have clear pleiotropic effects on reproduction, cancer, growth, and energy metabolism (50,51,52,53,54,55).

Coactivator Disease Alleles Are Predicted to Phenocopy Polygenic Disease

The most commonly held view of how polygenic disorders arise is that these diseases result from the accumulation of multiple disease-predisposing alleles that manifest phenotypically when present in a large enough quantity (Fig. 1B1B).). Disease-predisposing coactivator alleles are predicted to phenocopy polygenic disease despite arising from a single gene because of their ability to regulate the function of many genes in trans. This distributed effect on the expression of multiple downstream genes results in deleterious coactivator alleles that in turn mimic polygenic disease (Fig. 1C1C).

We also must consider that well over 300 coactivators have been identified in the literature, and of these, 165 have been implicated in human disease (19). Distinct disease-predisposing alleles in two or more coactivators within the same functional complex would be expected to weigh even heavier on a disease phenotype. Let us consider the members of the SRC-family of coactivators, for instance. SRC-1, SRC-2, and SRC-3 are known to participate in gene regulation as complexes with other co-coactivators such as coactivator-associated arginine methyltransferase-1 (CARM-1), CoCoA, p300, and PGC-1α (10,56), all of which are known to bind to SRCs and to functionally modify expression of target genes. Knowing that these proteins work together, we fully expect evidence to emerge that links them together in human polygenic disease because they have already been shown to cooperate in a biochemical sense (5,41,57,58). Along these lines, a number of human genetic studies have identified a relationship between certain coactivator polymorphisms and breast cancer, metabolism, and other pathologies (59,60,61,62,63,64,65,66). It should be cautioned that individually, many published associations between coactivator alleles and disease are suggestive at this point and require larger follow-up studies to provide more clarity. Future studies that examine the influence of inheritance of two or more predisposing coactivator alleles on a disease manifestation promise to strengthen the power to detect their role in human populations.

Can We Unravel the Composition of the Coactivator Complexes?

Biochemically, the pace of uncovering the role of coactivators in disease has been hampered by a reliance on reductionist approaches, studying one coactivator at a time. Fundamentally, coactivators are functionally interdependent proteins in multiprotein complexes. As a field, we have not directed sufficient emphasis toward unbiased proteomic approaches that would simultaneously uncover functional groupings of these proteins. However, systematic mass spectroscopic analyses of coactivator protein complexes are being carried out in a few centers at this time. We now are able to isolate steady-state transcriptional complexes and estimate their core constituent coactivator proteins (38,67,68,69). With this information in hand, we can begin to test how these coactivators work together as transcriptional control networks. This holistic understanding of how coactivators work together in aggregate is a central theme developed in the National Institutes of Health Nuclear Receptor Signaling Atlas (NURSA) project and is displayed on the NURSA electronic web site (NURSA.org).

SRC-2 Disruption Phenocopies Von Gierke's Disease

Are there experimental examples of a convergence between coactivators, pleiotropy, and polygenic disease? One recent example is illustrated by the finding that SRC-2 plays a key role in the expression of glucose 6-phosphatase (G6Pase). Von Gierke's disease is a genetically inherited glycogen storage disorder stemming from mutation of the G6Pase gene, the critical rate-limiting enzyme involved in the conversion of glycogen back into glucose (70). Because individuals with Von Gierke's disease are unable to break down glycogen, they suffer from dangerously low blood glucose levels upon fasting. SRC-2 knockout mice have been generated and characterized phenotypically. Consistent with its pleiotropic actions as a NR coactivator, disruption of the SRC-2 gene results in a complex phenotype, resulting in male and female hypofertility, resistance to obesity, and alterations in liver gene expression (47,55,71). In addition to this, its phenotype also overlaps with that seen in Von Gierke's disease. SRC-2 knockout mice become hypoglycemic under fasting conditions and a closer examination revealed that SRC-2 functions as a key coactivator responsible for the expression of G6Pase in the liver (52). Comparisons of the mouse G6Pase promoter revealed that it contains a conserved retinoid-related orphan receptor-α (RORα) response element (RORE) and that RORα can drive G6Pase gene transcription. Interestingly, the staggerer mutant mice that possess a spontaneous mutation of RORα possess a spectrum of metabolic defects (72), and it is interesting to speculate that this also stems from defects in the expression of G6Pase. Collectively, these observations reveal that genetic defects occurring at the level of a structural gene, a NR transcription factor, or a coactivator can all impact the appropriate regulation of glycogenolysis in response to fasting.

In keeping with the ideas discussed here, it is expected that mutations that disrupt G6Pase or RORα will be constitutive and deleterious. Because it functions within part of a larger multisubunit coactivator protein complex, mutation or allelism of SRC-2 is likely to be tolerated more than for G6Pase or RORα. SRC-2 allelism also is predicted to contribute more effectively to heritable changes that would be responsible for altered regulation of G6Pase that would be adaptive in a changing environment given SRC-2's role as an integrator of environmental and dietary signals. This leads us to propose a model that could be extended to the SRC family and other coactivators (Fig. 1C1C).). This model reflects the idea that alleles for different coactivator complex members combinatorially affect the function of the SRC coactivator protein complex and, in turn, the expression of its many target genes. For example, the SRC-3 complex in breast affects a large number of growth genes, whereas the SRC-1 complex in liver affects multiple gluconeogenic genes (73). We predict that allelism among the members of a coactivator complex are more likely to be tolerated and seen in human populations than are the more severe alleles for NRs.

Conclusions

Coactivator genes, like all others, are products of natural selection. We argue here that SRC family coactivators serve prominent roles as genes subject to strong positive selection pressure due to their roles as master regulators and integrators of a broad range of signals from our environment. The abrupt trajectory of our short history on Earth as a species has put us at odds with the environment in which we were meant to live. Thus, we posit that in a polygenic sense, numerous weakly penetrant cis-acting alleles and broadly acting pleiotropic coactivator alleles both contribute in trans to the advent of many modern diseases. This process may have required a greater length of time to accumulate the multiple polygenic alleles needed to confer an adaptive advantage. Because coactivators are predicted to be the evolutionary first responders, receiving posttranslational modifications from signaling pathways and influencing the expression of many genes in a coordinated manner through the change of a single allele would be advantageous. Two other interlocking elements in this model are that as master regulator genes, SRC family coactivators are weakly penetrant themselves, allowing them the flexibility to continue to evolve in accordance with changes in our environment. Their weak penetrance is due to the fact that they work as part of multiprotein coactivator complexes. Each coactivator has a fractional role in promoting transcription such that the loss of function in any single coactivator does not result in lethality. Ultimately, we expect that future advances in genome-wide association studies and in high-throughput proteomics will help to prove and extend the generality of the concepts presented here. With this information in hand, we soon should be able to understand how coactivator proteins and complexes fulfill their roles as master regulators at the nexus between metabolism, reproduction, cancer, other human diseases, and our environment.

Footnotes

This work was performed with funding from the National Institutes of Health (HD 07857 and HD 08819) to B.W.O.

Disclosure Summary: The authors have nothing to disclose.

First Published Online October 21, 2009

Abbreviations: G6Pase, Glucose 6-phosphatase; NR, nuclear receptor; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator-1α; PTM, posttranslational modification; RORα, retinoid-related orphan receptor-α; SRC, steroid receptor coactivator.

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