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Research Article

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

Maria Suntsova, Elena V. Gogvadze, Sergey Salozhin, Nurshat Gaifullin, Fedor Eroshkin, Sergey E. Dmitriev, Natalia Martynova, Kirill Kulikov, Galina Malakhova, Gulnur Tukhbatova, Alexey P. Bolshakov, Dmitry Ghilarov, Andrew Garazha, Alexander Aliper, Charles R. Cantor, Yuri Solokhin, Sergey Roumiantsev, Pavel Balaban, Alex Zhavoronkov, and Anton Buzdin
  1. aGroup for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia;
  2. bLaboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow 117198, Russia;
  3. cLaboratory of Molecular Neurobiology, Institute of Higher Nervous Activity and Neurophysiology, Moscow 117485, Russia;
  4. dFaculty of Fundamental Medicine and
  5. fBelozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119192, Russia;
  6. eDepartment of Pathology, Russian National Research Medical University named after N. I. Pirogov, Moscow 117997, Russia; and
  7. gDepartment of Biomedical Engineering, Boston University, Boston, MA 02215

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PNAS first published November 11, 2013; https://doi.org/10.1073/pnas.1318172110
Maria Suntsova
aGroup for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia;
bLaboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow 117198, Russia;
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Elena V. Gogvadze
aGroup for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia;
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Sergey Salozhin
cLaboratory of Molecular Neurobiology, Institute of Higher Nervous Activity and Neurophysiology, Moscow 117485, Russia;
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Nurshat Gaifullin
dFaculty of Fundamental Medicine and
eDepartment of Pathology, Russian National Research Medical University named after N. I. Pirogov, Moscow 117997, Russia; and
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Fedor Eroshkin
aGroup for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia;
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Sergey E. Dmitriev
fBelozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119192, Russia;
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Natalia Martynova
aGroup for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia;
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Kirill Kulikov
eDepartment of Pathology, Russian National Research Medical University named after N. I. Pirogov, Moscow 117997, Russia; and
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Galina Malakhova
aGroup for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia;
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Gulnur Tukhbatova
cLaboratory of Molecular Neurobiology, Institute of Higher Nervous Activity and Neurophysiology, Moscow 117485, Russia;
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Alexey P. Bolshakov
cLaboratory of Molecular Neurobiology, Institute of Higher Nervous Activity and Neurophysiology, Moscow 117485, Russia;
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Dmitry Ghilarov
aGroup for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia;
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Andrew Garazha
aGroup for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia;
bLaboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow 117198, Russia;
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Alexander Aliper
aGroup for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia;
bLaboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow 117198, Russia;
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Charles R. Cantor
gDepartment of Biomedical Engineering, Boston University, Boston, MA 02215
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  • For correspondence: ccantor@sequenom.com bu3din@mail.ru
Yuri Solokhin
eDepartment of Pathology, Russian National Research Medical University named after N. I. Pirogov, Moscow 117997, Russia; and
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Sergey Roumiantsev
bLaboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow 117198, Russia;
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Pavel Balaban
cLaboratory of Molecular Neurobiology, Institute of Higher Nervous Activity and Neurophysiology, Moscow 117485, Russia;
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Alex Zhavoronkov
bLaboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow 117198, Russia;
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Anton Buzdin
aGroup for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia;
bLaboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow 117198, Russia;
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  • For correspondence: ccantor@sequenom.com bu3din@mail.ru
  1. Contributed by Charles R. Cantor, October 19, 2013 (sent for review August 2, 2013)

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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.

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Retroviral DNA serves as enhancer for PRODH gene
Maria Suntsova, Elena V. Gogvadze, Sergey Salozhin, Nurshat Gaifullin, Fedor Eroshkin, Sergey E. Dmitriev, Natalia Martynova, Kirill Kulikov, Galina Malakhova, Gulnur Tukhbatova, Alexey P. Bolshakov, Dmitry Ghilarov, Andrew Garazha, Alexander Aliper, Charles R. Cantor, Yuri Solokhin, Sergey Roumiantsev, Pavel Balaban, Alex Zhavoronkov, Anton Buzdin
Proceedings of the National Academy of Sciences Nov 2013, 201318172; DOI: 10.1073/pnas.1318172110

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Retroviral DNA serves as enhancer for PRODH gene
Maria Suntsova, Elena V. Gogvadze, Sergey Salozhin, Nurshat Gaifullin, Fedor Eroshkin, Sergey E. Dmitriev, Natalia Martynova, Kirill Kulikov, Galina Malakhova, Gulnur Tukhbatova, Alexey P. Bolshakov, Dmitry Ghilarov, Andrew Garazha, Alexander Aliper, Charles R. Cantor, Yuri Solokhin, Sergey Roumiantsev, Pavel Balaban, Alex Zhavoronkov, Anton Buzdin
Proceedings of the National Academy of Sciences Nov 2013, 201318172; DOI: 10.1073/pnas.1318172110
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