When thinking about the evolution of female and male, consider that the first steroid receptor proteins, which emerged about 550 million years ago, were responsive to estrogen. The ancestor of other steroid hormone receptors, responsive to hormones such as testosterone, progesterone and cortisol, emerged many millions of years later.
Blue = estrogen-responsive receptors, Orange = non-aromatized (progesterone, testosterone, cortisol) hormone-responsive
Biochemist Eric Ortlund and colleagues have a new paper in Structure that reconstructs how interactions of steroid receptor proteins evolved over time. This is a complex area to model, since the receptors change shape when they bind their respective hormones, allowing them to bring in other proteins and activate genes.
First author C. Denise Okafor, a FIRST postdoctoral fellow at Emory, will be starting a position as assistant professor at Penn State next month.
The scientists also show that a mutation in the mineralocorticoid receptor associated with severe hypertension (S810L), which makes the receptor more promiscuous, restores an ancestral interaction within the protein.
“Evolutionary substitutions rewired the networks, subsequently altering hormonal interactions and allowing steroid receptors to achieve ligand specificity over time,” the authors write.
It arises from what scientists previously described as “junk DNA” or “the dark matter of the genome,” but this gene is definitely not junk. The gene Gas5 acts as a brake on steroid hormone receptors, making it a key player in diseases such as hormone-sensitive prostate and breast cancer.
Unlike many genes scientists are familiar with, Gas5 does not encode a protein. It gets transcribed into RNA, like many other genes, but with Gas5 the RNA is what’s important, not the protein. The RNA accumulates in cells subjected to stress and soaks up steroid hormone receptors, preventing them from binding DNA and turning genes on and off.
Emory researchers have obtained a detailed picture of how the Gas5 RNA interacts with steroid hormone receptors. Their findings show how the Gas5 RNA takes the place of DNA, and give hints as to how it evolved.
The results were published Friday in Nature Communications.
Scientists used to think that much of the genome was “fly-over country”: not encoding any protein and not even accessed much by the cell’s gene-reading machinery. Recent studies have revealed that a large part of the genome is copied into lincRNAs (long intergenic noncoding RNAs), of which Gas5 is an example. Read more