Human-specific endogenous retroviral insert serves as an enhancer for the schizophrenia-linked gene PRODH

Abstract

Using a systematic, whole-genome analysis of enhancer activity of human-specific endogenous retroviral inserts (hsERVs), we identified an element, hsERV PRODH , 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 hsERV PRODH enhancer activity. We showed that the hsERV PRODH enhancer and the internal CpG island of PRODH synergistically activate its promoter. The enhancer activity of hsERV PRODH is regulated by methylation, and in an undermethylated state it can up-regulate PRODH expression in the hippocampus. The mechanism of hsERV PRODH enhancer activity involves the binding of the transcription factor SOX2, whch is preferentially expressed in hippocampus. We propose that the interaction of hsERV PRODH and PRODH may have contributed to human CNS evolution.human-specific endogenous retrovirus | DNA methylation | central nervous system | human speciation | retroelement U nderstanding the molecular basis of phenotypic differences between humans and chimpanzees can provide important clues to human-specific behavioral peculiarities and neurological disorders. For this purpose we conducted a genome-wide analysis of human-specific endogenous retroviral (hsERV) inserts that may induce new regulatory pathways by acting as promoters and enhancers (1, 2). HsERVs of the HERV-K(HML-2) group are one of the four families of transposable elements that were able to transpose at the time of the radiation of human lineage from the lineage of its most closely related species, chimpanzee (3). At least 50% of all hsERV elements exhibit promoter activity in human tissues (4). We found only six hsERV inserts in the upstream regions of known human genes, close to transcription start sites. Three of them displayed strong enhancer activity in transient transfection experiments; of these three, only one-near the PRODH gene-matched the transcriptional activity pattern of its endogenous genomic copy. This copy of hsERV is a full-length, almost intact betaretrovirus belonging to the HERV-K(HML-2) group. PRODH encodes a mitochondrial enzyme proline, dehydrogenase (oxidase), that converts proline to D-1-pyrroline-5-carboxylate (5). PRODH regulates proline catabolism, which is vital for normal CNS functioning. Several PRODH mutations are associated with neuropsychiatric disorders, such as schizophrenia (6). Gene knockouts in mice cause severe changes in the executive functioning of the brain (7). Given the potential importance of PRODH in brain functioning and disease, we attempted to characterize its newly recognized hsERV PRODH enhancer. We showed that hsERV PRODH enhancer activity is regulated by methylation and that the hsERV PRODH enhancer and PRODH internal CpG island act syne...

Molecular functions of human endogenous retroviruses in health and disease

“…Solitary LTRs are differentially methylated in different human tissues [39][40][41], they may specifically bind host cell nuclear proteins [42,43], serve as tissue-specific transcriptional promoters and enhancers [4,26,39,44], and, finally, are transcribed in vivo in many tissues [1,[45][46][47][48]. In addition, LTRs may contribute to the host gene regulation network by acting in cis (by providing regulatory elements) or in trans (by driving expression of antisense transcripts) [30,[48][49][50][51].…”

“…Even the physical presence of such a number of repetitive sequences in the genome can generate considerable problems dealing with homologous recombination between the different HERV elements, which may disrupt functional genes located in their neighborhood [10]. HERV-derived transcription and gene regulation can bias normal gene expression regulatory networks [4,10,48]. Expression of HERV proteins in various human tissues may result in dangerous inflammatory or immunosuppressive effects [35].…”

“…Genomic copies of HERVs are of particular interest because in addition to functional viral genes, they have multitude of regulatory DNA regions serving as promoters [1][2][3], enhancers [4,5], polyadenylation signals [6,7], insulators [8,9] and binding sites for various nuclear proteins [2,[10][11][12][13]. Many families of HERVs exhibit high transcriptional activity in human tissues [1,[14][15][16][17].…”

Human Endogenous Retroviruses

“…Many transcription regulating elements including transcription initiating and terminating signals are located in LTR sequences. The LTR serves as enhancers (Suntsova et al, 2013), promoters (Buzdin et al, 2006), polyadenylation signals (Suntsova et al, 2015) and binding sites for several nuclear proteins (Schulman et al, 2010). These structures are comparatively frequent in the human genome and it is assumed that they influenced evolution of the primate genome via transposition, translocation and recombination (Paces et al, 2013).…”

Do the Human Endogenous Retroviruses Play a Role in Colon Cancer?

“…24 Another example is given by the insertion of the HERV-K LTR, creating an enhancer element for the human gene PRODH that has a strong implication in higher nervous activity in hippocampus. 25 Again, ERVL TLR promotes the transcription of the human gene b3GAL-T5 that concurs to the synthesis of type 1 carbohydrate chains, expecially in colon. 26 HERV LTR was also shown to regulate the transcription of the BIRC1 gene that encodes a neuronal apoptosis inhibitory factor.…”