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TDP-43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting R-loop and 5hmC crosstalk
- Source :
- Cell Reports, Vol 43, Iss 1, Pp 113662- (2024)
- Publication Year :
- 2024
- Publisher :
- Elsevier, 2024.
-
Abstract
- Summary: TDP-43 is an RNA/DNA-binding protein that forms aggregates in various brain disorders. TDP-43 engages in many aspects of RNA metabolism, but its molecular roles in regulating genes and transposable elements (TEs) have not been extensively explored. Chronic TDP-43 knockdown impairs cell proliferation and cellular responses to DNA damage. At the molecular level, TDP-43 chronic deficiency affects gene expression either locally or distally by concomitantly altering the crosstalk between R-loops and 5-hydroxymethylcytosine (5hmC) in gene bodies and long-range enhancer/promoter interactions. Furthermore, TDP-43 knockdown induces substantial disease-relevant TE activation by influencing their R-loop and 5hmC homeostasis in a locus-specific manner. Together, our findings highlight the genomic roles of TDP-43 in modulating R-loop-5hmC coordination in coding genes, distal regulatory elements, and TEs, presenting a general and broad molecular mechanism underlying the contributions of proteinopathies to the etiology of neurodegenerative disorders.
- Subjects :
- CP: Neuroscience
Biology (General)
QH301-705.5
Subjects
Details
- Language :
- English
- ISSN :
- 22111247
- Volume :
- 43
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- Cell Reports
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.3ab588af9f204653a142849fac412e36
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.celrep.2023.113662