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

被引：61

作者：

Suntsova, Maria ^{[1
,2
]}

Gogvadze, Elena V. ^{[1
]}

Salozhin, Sergey ^{[3
]}

Gaifullin, Nurshat ^{[4
,6
]}

Eroshkin, Fedor ^{[1
]}

Dmitriev, Sergey E. ^{[5
]}

Martynova, Natalia ^{[1
]}

Kulikov, Kirill ^{[6
]}

Malakhova, Galina ^{[1
]}

Tukhbatova, Gulnur ^{[3
]}

Bolshakov, Alexey P. ^{[3
]}

Ghilarov, Dmitry ^{[1
]}

Garazha, Andrew ^{[1
,2
]}

Aliper, Alexander ^{[1
,2
]}

Cantor, Charles R. ^{[7
]}

Solokhin, Yuri ^{[6
]}

Roumiantsev, Sergey ^{[2
]}

Balaban, Pavel ^{[3
]}

Zhavoronkov, Alex ^{[2
]}

Buzdin, Anton ^{[1
,2
]}

机构：

[1] Shemyakin Ovchinnikov Inst Bioorgan Chem, Grp Genom Regulat Cell Signaling Syst, Moscow 117997, Russia

[2] D Rogachyov Fed Res Ctr Pediat Hematol Oncol & Im, Lab Bioinformat, Moscow 117198, Russia

[3] Inst Higher Nervous Act & Neurophysiol, Mol Microbiol Lab, Moscow 117485, Russia

[4] Moscow MV Lomonosov State Univ, Fac Fundamental Med, Moscow 119192, Russia

[5] Moscow MV Lomonosov State Univ, Belozersky Inst Physicochem Biol, Moscow 119192, Russia

[6] Russian Natl Res Med Univ, Dept Pathol, Moscow 117997, Russia

[7] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 48期

关键词：

human-specific endogenous retrovirus; DNA methylation; central nervous system; human speciation; retroelement; LONG TERMINAL REPEATS; TRANSCRIPTIONAL ACTIVITY; CPG METHYLATION; PROLINE; HYPERPROLINEMIA; EXPRESSION; DEHYDROGENASE; ASSOCIATION; INITIATION; PROMOTER;

D O I：

10.1073/pnas.1318172110

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 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.

引用

页码：19472 / 19477

页数：6

共 10 条

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