Project Details
Projekt
Regulation and function of the ERV-lncRNAs in postmitotic neurons
Applicant
Dr. Kyung Min Noh
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Term
from 2017 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 389581024
The precise mechanisms underlying stimulation induced neuronal maturation and plasticity have been subject to studies at the molecular, cellular and neuronal network levels and are likely to involve a combination of changes in gene expression, protein synthesis and cellular/anatomical structure. In recent years, there has been an extensive search for gene regulatory mechanisms that respond within short timescales to promote initial acquisition, while persisting over longer timescales to allow for long-term consolidation. This has prompted much interest in the process of chromatin regulation that is not hardwired in DNA itself. Exciting new research suggests that regulatory elements including long noncoding RNAs (lncRNAs) are responsible for mediating such changes. Endogenous retrovirus (ERV) mediated gene regulation and chromatin remodeling via the production of lncRNAs (ERV-lncRNAs) is an emerging topic. Our central hypothesis is that external stimuli experienced during postmitotic neuronal maturation generate robust changes in specific lncRNA profiles, such that comprehensive analyses of ERV-lncRNAs expression and regulatory network promise to provide fundamentally novel insights into the gene expression mechanism orchestrating normal brain cell response and neurological disease. We seek to test this working hypothesis in the following three interrelated Specific Aims: 1) Studies of ERVs-lncRNAs regulation in postmitotic neurons in the presence and absence of external stimulation. We aim to perform state-of-the-art genome and epigenome sequencing to explore potential novel links between the lncRNAs regulatory network and patterns of gene expression in the context of postmitotic neurons followed by external stimulation. 2) Determine the functional relevance of a target ERV-lncRNA. We aim to use our developed/progressing methods to manipulate a specific ERV-lncRNA expression in postmitotic neurons, via both loss-of-function and gain-of-function studies, to determine its causal role in altering gene expression. 3) Studies of the impact of ATRX on ERV-lncRNAs expression in neurons. We propose to extend our work on ERV-lncRNAs in stimulated neurons to the disease paradigm by examining the impact of ATRX, a member of chromatin remodeling factors whose loss-of-function mutations cause a complex neurological syndrome, on ERV-lncRNAs expression. Collectively our studies will provide novel and critical information regarding the epigenome regulation across neuronal activation. Identification of genes and gene networks with altered chromatin status will help to better describe the epigenetic landscape during critical period of neuronal activation. Such new knowledge has the potential to lead to the development of novel treatments aimed at reducing the progression of neurological illnesses.
DFG Programme
Priority Programmes
