Trichoplax, the simplest known animal, contains an estrogen-related receptor but no estrogen receptor: Implications for estrogen receptor evolution

doi:10.1016/j.bbrc.2008.08.047

Biochemical and Biophysical Research Communications

Volume 375, Issue 4, 31 October 2008, Pages 623-627

https://doi.org/10.1016/j.bbrc.2008.08.047 Get rights and content

Abstract

Although, as their names imply, estrogen receptors [ERs] and estrogen-related receptors [ERRs] are related transcription factors, their evolutionary relationships to each other are not fully understood. To elucidate the origins and evolution of ERs and ERRs, we searched for their orthologs in the recently sequenced genome of Trichoplax, the simplest known animal, and in the genomes of three lophotrochozoans: Capitella, an annelid worm, Helobdella robusta, a leech, and Lottia gigantea, a snail. BLAST searches found an ERR in Trichoplax, but no ER. BLAST searches also found ERRs in all three lophotrochozoans and invertebrate-like ERs in Capitella and Lottia, but not in Helobdella. Unexpectedly we find that the Capitella ER sequence is closest to ERβ, unlike the other invertebrate ER sequences, which are closest to ERα. Our database searches and phylogenetic analysis indicate that invertebrate ERs evolved in a lophotrochozoan and steroid-binding ERs evolved in a deuterostome.

Section snippets

Materials and methods

BLAST [33] was used to collect ERR and ER sequences from the JGI server [http://genome.jgi-psf.org] and GenBank. Two different methods, Clustal X 2.0 [34], which uses a neighbor-joining algorithm [35], and PHYML [36], which uses a maximum likelihood algorithm, were used to construct phylogenetic trees of various ERs, ERRs, human retinoid X receptor-α (RXRα) and amphioxus RXR.

For the Clustal X 2.0 phylogeny, the multiple alignments of ERs, ERRs and RXRs were done using the iteration option for

Four nuclear receptors are present in a basal diploblast

The DNA and ligand-binding domains of human ERRγ, human ERα, octopus ER, Aplysia ER, Thais ER and oyster ER were used as queries for BLAST searches for orthologs in Trichoplax, Capitella, Helobdella, and Lottia on the JGI server. The BLAST search of Trichoplex with human ERRγ yielded four high scoring nuclear receptors. Searches with human ERα and invertebrate ERs found the same genes in Trichoplax. To classify the four Trichoplax genes, we used their sequences as queries for BLAST searches of

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Sequence analysis indicates that nuclear receptors are not present in yeast or plants. Nuclear receptors have been found in basal metazoans: sponges (Porifera) (Bridgham et al., 2010) and Trichoplax adhaerens (Placazoa) (Baker, 2008; Khalturin et al., 2018; Novotny et al., 2017; Reitzel et al., 2018), which contain two and four nuclear receptors, respectively. Trichoplax has an estrogen related receptor γ (ERRγ), a retinoid X receptor (RXR), a chicken ovalbumin upstream promoter receptor (COUP) and an Hepatocyte Nuclear Factor 4 receptor (HNF4).
Considering that life on earth evolved about 3.7 billion years ago, vertebrates are young, appearing in the fossil record during the Cambrian explosion about 542 to 515 million years ago. Results from sequence analyses of genomes from bacteria, yeast, plants, invertebrates and vertebrates indicate that receptors for adrenal steroids (aldosterone, cortisol), and sex steroids (estrogen, progesterone, testosterone) also are young, with an estrogen receptor and a 3-ketosteroid receptor first appearing in basal chordates (cephalochordates: amphioxus), which are close ancestors of vertebrates. Duplication and divergence of the 3-ketosteroid receptor yielded an ancestral progesterone receptor and an ancestral corticoid receptor, the common ancestor of the glucocorticoid and mineralocorticoid receptors, in jawless vertebrates (cyclostomes: lampreys, hagfish). This was followed by evolution of an androgen receptor, distinct glucocorticoid and mineralocorticoid receptors and estrogen receptor-α and -β in cartilaginous fishes (Chondrichthyes: sharks). Further evolution of mineralocorticoid signaling occurred with the evolution of aldosterone synthase in lungfish, a forerunner of terrestrial vertebrates. Adrenal and sex steroid receptors are not found in echinoderms and hemichordates, which are ancestors in the lineage of cephalochordates and vertebrates. The evolution of steroid receptors at key nodes in the evolution of vertebrates, in which steroid receptors act as master switches to regulate differentiation, development, reproduction, immune responses, electrolyte homeostasis and stress responses, suggests an important role for steroid receptors in the evolutionary success of vertebrates, considering that the human genome contains about 22,000 genes, which is not much larger than genomes of invertebrates, such as Caenorhabditis elegans (~18,000 genes) and Drosophila (~14,000 genes).
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Present-day nuclear receptors (NRs) responding to adrenal and sex steroids are key regulators of reproduction and growth in mammals, and are thought to have evolved from an ancestral NR most closely related to extant estrogen-related receptors (ERRs). The molecular events (and ligands) that distinguish steroid-activated NRs (SRs) from their inferred ancestor, that gave rise to both the ERRs and SRs, remain unknown. We report that target sequences for fatty-acylation (palmitoylation) at a key cysteine residue (corresponding to Cys447 in human estrogen receptor ERα) in helix 8 of the ligand-binding domain accurately demarcate SRs from ERRs. Docking studies are consistent with the hypothesis that palmitate embeds into a key groove in the receptor surface. The implications of lipidation, and of potential alternative ligands for the key cysteine residue, for receptor function and the evolution of SRs are discussed.
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Many actions of estradiol (E2), the principal physiological estrogen in vertebrates, are mediated by estrogen receptor-α (ERα) and ERβ. An important physiological feature of vertebrate ERs is their promiscuous response to several physiological steroids, including estradiol (E2), Δ⁵-androstenediol, 5α-androstanediol, and 27-hydroxycholesterol. A novel structural characteristic of Δ⁵-androstenediol, 5α-androstanediol, and 27-hydroxycholesterol is the presence of a C19 methyl group, which precludes the presence of an aromatic A ring with a C3 phenolic group that is a defining property of E2. The structural diversity of these estrogens can explain the response of the ER to synthetic chemicals such as bisphenol A and DDT, which disrupt estrogen physiology in vertebrates, and the estrogenic activity of a variety of plant-derived chemicals such as genistein, coumestrol, and resveratrol. Diversity in the A ring of physiological estrogens also expands potential structures of industrial chemicals that can act as endocrine disruptors. Compared to E2, synthesis of 27-hydroxycholesterol and Δ⁵-androstenediol is simpler, leading us, based on parsimony, to propose that one or both of these steroids or a related metabolite was a physiological estrogen early in the evolution of the ER, with E2 assuming this role later as the canonical estrogen. In addition to the well-studied role of the ER in reproductive physiology, the ER also is an important transcription factor in non-reproductive tissues such as the cardiovascular system, kidney, bone, and brain. Some of these ER actions in non-reproductive tissues appeared early in vertebrate evolution, long before the emergence of mammals.

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Trichoplax, the simplest known animal, contains an estrogen-related receptor but no estrogen receptor: Implications for estrogen receptor evolution

Abstract

Section snippets

Materials and methods

Four nuclear receptors are present in a basal diploblast

Trends Endocrinol. Metab.

J. Biol. Chem.

Mol. Cell. Endocrinol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell

Trends Cell Biol.

J. Biol. Chem.

Trends Biochem. Sci.

Trends Endocrinol. Metab.

Cell Metab.

Gen. Comp. Endocrinol.

Gen. Comp. Endocrinol.

Biochem. Biophys. Res. Commun.

Dev. Biol.

Identification of a new class of steroid hormone receptors

Nature

Estrogen receptor-related receptors: orphan receptors desperately seeking a ligand

J. Mol. Endocrinol.

Orphan nuclear receptors: shifting endocrinology into reverse

Science

Seeking ligands for lonely orphan receptors

Science

Ligand binding and nuclear receptor evolution

Bioessays

Evolutionary genomics of nuclear receptors: from twenty-five ancestral genes to derived endocrine systems

Mol. Biol. Evol.