Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Contributed by Charles R. Cantor, October 19, 2013 (sent for review August 2, 2013)
Significance
We identified a human-specific endogenous retroviral insert (hsERV) that acts as an enhancer for human PRODH, hsERV_PRODH. PRODH encodes proline dehydrogenase, which is involved in neuromediator synthesis in the CNS. We show that the hsERV_PRODH enhancer acts synergistically with the CpG island of PRODH and is regulated by methylation. We detected high PRODH expression in the hippocampus, which was correlated with the undermethylated state of this enhancer. PRODH regulatory elements provide neuron-specific transcription in hippocampal cells, and the mechanism of hsERV_PRODH enhancer activity involves the binding of transcriptional factor SOX2. Because PRODH is associated with several neurological disorders, we hypothesize that the human-specific regulation of PRODH by hsERV_PRODH may have played a role in human evolution by upregulating the expression of this important CNS-specific gene.
Abstract
Using a systematic, whole-genome analysis of enhancer activity of human-specific endogenous retroviral inserts (hsERVs), we identified an element, hsERVPRODH, that acts as a tissue-specific enhancer for the PRODH gene, which is required for proper CNS functioning. PRODH is one of the candidate genes for susceptibility to schizophrenia and other neurological disorders. It codes for a proline dehydrogenase enzyme, which catalyses the first step of proline catabolism and most likely is involved in neuromediator synthesis in the CNS. We investigated the mechanisms that regulate hsERVPRODH enhancer activity. We showed that the hsERVPRODH enhancer and the internal CpG island of PRODH synergistically activate its promoter. The enhancer activity of hsERVPRODH is regulated by methylation, and in an undermethylated state it can up-regulate PRODH expression in the hippocampus. The mechanism of hsERVPRODH enhancer activity involves the binding of the transcription factor SOX2, whch is preferentially expressed in hippocampus. We propose that the interaction of hsERVPRODH and PRODH may have contributed to human CNS evolution.
- human-specific endogenous retrovirus
- DNA methylation
- central nervous system
- human speciation
- retroelement
Footnotes
- ↵1To whom correspondence may be addressed. E-mail: ccantor{at}sequenom.com or bu3din{at}mail.ru.
Author contributions: M.S., E.V.G., S.S., F.E., S.E.D., A.P.B., C.R.C., Y.S., S.R., P.B., A.Z., and A.B. designed research; M.S., E.V.G., N.G., F.E., S.E.D., N.M., K.K., G.M., G.T., A.P.B., D.G., A.G., A.A., Y.S., and A.B. performed research; M.S., E.V.G., S.S., S.E.D., A.G., A.A., C.R.C., S.R., A.Z., and A.B. analyzed data; and M.S., E.V.G., S.S., S.E.D., C.R.C., S.R., A.Z., and A.B. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1318172110/-/DCSupplemental.
Retroviral DNA serves as enhancer for PRODH gene
Sign up for Article Alerts
Jump to section
You May Also be Interested in
Did the Caribbean sweep into the western Amazon millions of years ago, shaping the region’s rich biodiversity?
Image credit: Tacio Cordeiro Bicudo (University of São Paulo, São Paulo, Brazil), Victor Sacek (University of São Paulo, São Paulo, Brazil), and Lucy Reading-Ikkanda (artist).
Settlements 4,200 years ago may have suffered from overpopulation before drought and lower temperatures ultimately made them unsustainable.
Image credit: Andrea Ricci.
Mara Reed and Michael Manga explore why Yellowstone's Steamboat Geyser resumed erupting in 2018.
Some songbird parents might improve their own fitness by manipulating their offspring into leaving the nest early, at the cost of fledgling survival, a study finds.
Image credit: Gil Eckrich (photographer).