Long interspersed nuclear element 1 (LINE-1 or L1) is a family of non-LTR retrotransposons that can replicate and reinsert into the host genome. L1s have considerably influenced mammalian genome evolution by retrotransposing during germ cell development and early embryogenesis. Integration within genes has caused mutagenesis leading to genetic diseases. Historically, L1s were thought to only retrotranspose during gametogenesis and in neoplastic processes, but recent studies have shown L1s are extremely active in the mouse, rat, and human neuronal progenitor cells (NPCs). In fact, the hippocampus and other regions of the brain have approximately 80 de novo L1 integration events per cell when compared to the heart and liver. If these integration events are not properly regulated, they could cause gene mutagenesis. Methyl-CpG-binding protein 2 (MeCP2), associated with Rett Syndrome (RTT), is a major regulator of L1 elements in neurons. In fact, neurons lacking the protein MeCP2 have more L1 retrotransposition events and cannot properly regulate the newly integrated L1 DNA, possibly giving rise to some of the phenotypes seen in RTT individuals. Understanding the biology of MeCP2 regulation of L1 expression and integration will yield insight into one of the most puzzlingly genetic diseases. We hypothesize MeCP2 tightly controls L1 integration events in neurons. Furthermore, in neurons devoid of functional MeCP2, the control of L1 mutagenesis is lost, contributing to improper neuronal function in of RTT patients. To test these hypotheses, we have three specific aims: 1) to reveal the mechanistic interaction and regulation of MeCP2 on LINE-1 transcription, retrotransposition, and post-integration silencing during neuronal differentiation;2) to discover the genomic sites of LINE- 1 mutagenesis in RTT neurons;and 3) to determine the stereotypic RTT neuronal phenotypes directly attributed to LINE-1 retrotransposition. Achieving these specific aims will begin to assign some aspects of the complex and large spectrum of phenotypes described in RTT patients to specific molecular phenomena of neurons. Furthermore, unveiling the consequence of L1 integration events in the context of wild-type and RTT NPCs on the nervous system could help explain the heterogeneity of RTT phenotypes and behavior.

Public Health Relevance

The retroelement LINE-1 causes major mutagenesis in the genomes of Rett Syndrome neurons. Mutagenesis in the neurons of Rett Syndrome patients likely results in some of the neuronal abnormalities and malformations commonly associated with the syndrome. Elucidating the mechanism of MeCP2 regulation of LINE-1 mutagenesis will attribute some of the Rett neuronal phenotypes with a specific molecular phenomenon, possibly leading to future therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS076198-02
Application #
8467592
Study Section
Special Emphasis Panel (ZRG1-F03B-G (20))
Program Officer
Mamounas, Laura
Project Start
2012-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$34,942
Indirect Cost
Name
University of California San Diego
Department
None
Type
Other Domestic Higher Education
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093