TRIM28 Represses Transcription of Endogenous Retroviruses in Neural Progenitor Cells

Liana Fasching, Adamandia Kapopoulou, Rohit Sachdeva, Rebecca Petri, Marie E. Jönsson, Christian Männe, Priscilla Turelli, Patric Jern, Florence Cammas, Didier Trono, and Johan Jakobsson

Cell Rep. 10(1):20-28. 2015 Jan.

Speaker : Fang-Wei Liao (廖芳緯)                               Time : 14:10-15:00, Jun. 17, 2015

Commentator : Ai-Li Shiau, Ph.D. (蕭璦莉 老師)     Place : Room 601

Abstract:

　　Around 8-10% of human and murine DNA genomes consist of endogenous retroviruses (ERVs) as provirus forms. Rather than “junk DNA”, ERVs may serve as transcriptional start sites orcis-acting regulatory elements for the host genomes. During the first days of embryogenesis, activity of ERVs is suppressed by a transcriptional corepressor, tripartite motif-containing protein 28 (TRIM28), which induces repressive histone modifications and transcription silencing. Thereafter ERV suppression is generally taken over by DNA methylation, which causes stable ERV silencing. Interestingly, ERVs are not stably silenced in neural progenitor cells (NPCs) and during brain development, so the authors speculated that TRIM28 remains in charge of ERV control therein. They established tissue-specific gene-knockout mice where Trim28 was excised in NPCs. Trim28 knockout did not influence self renewal and differentiation of NPCs. Notably, transcription of several ERVs, such as MMERVK10C and intracisternal A-particles class 1 (IAP1), was highly reactivated in Trim28^-/- NPCs. The reactivated ERV genomes showed reduced repressive histone methylation (H3K9me3) without change in DNA methylation patterns, supporting that ERVs in NPC are controlled by TRIM28-mediated epigenetic silencing rather than DNA methylation. Notably, ERV reactivation in Trim28^-/- NPCs was accompanied by increased transcription of adjacent genes and nearby long noncoding RNAs (lncRNAs), suggesting that ERV reactivation influences host gene expression. Considering the facts that Trim28 knockout in adult mouse forebrain results in complex behavioral alterations^[1] and that ERV reactivation is detected in patients with neurological and psychiatric disorders,^[2] the authors propose a potential link of TRIM28-regulated ERVs to neuronal development.

References:

1.         Jakobsson J, Cordero MI, Bisaz R, Groner AC, Busskamp V, Bensadoun JC, Cammas F, Losson R, Mansuy IM, Sandi C, Trono D. 2008. KAP1-mediated epigenetic repression in the forebrain modulates behavioral vulnerability to stress. Neuron. 60(5):818-31.

2.         Renée Douville, Jiankai Liu, Jeffrey Rothstein, Avindra Nath. 2011. Identification of Active Loci of a Human Endogenous Retrovirus in Neurons of Patients with Amyotrophic Lateral Sclerosis. Ann Neurol. 69(1):141-151.