TDP-43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting R-loop and 5hmC crosstalk
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 prol...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472301673X |
| _version_ | 1797362600763195392 |
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| author | Yingzi Hou Yangping Li Jian-Feng Xiang Kedamawit Tilahun Jie Jiang Victor G. Corces Bing Yao |
| author_facet | Yingzi Hou Yangping Li Jian-Feng Xiang Kedamawit Tilahun Jie Jiang Victor G. Corces Bing Yao |
| author_sort | Yingzi Hou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T16:09:10Z |
| format | Article |
| id | doaj.art-3ab588af9f204653a142849fac412e36 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-08T16:09:10Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-3ab588af9f204653a142849fac412e362024-01-08T04:07:25ZengElsevierCell Reports2211-12472024-01-01431113662TDP-43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting R-loop and 5hmC crosstalkYingzi Hou0Yangping Li1Jian-Feng Xiang2Kedamawit Tilahun3Jie Jiang4Victor G. Corces5Bing Yao6Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USADepartment of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USADepartment of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USADepartment of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USADepartment of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USADepartment of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USADepartment of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S221112472301673XCP: Neuroscience |
| spellingShingle | Yingzi Hou Yangping Li Jian-Feng Xiang Kedamawit Tilahun Jie Jiang Victor G. Corces Bing Yao TDP-43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting R-loop and 5hmC crosstalk Cell Reports CP: Neuroscience |
| title | TDP-43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting R-loop and 5hmC crosstalk |
| title_full | TDP-43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting R-loop and 5hmC crosstalk |
| title_fullStr | TDP-43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting R-loop and 5hmC crosstalk |
| title_full_unstemmed | TDP-43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting R-loop and 5hmC crosstalk |
| title_short | TDP-43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting R-loop and 5hmC crosstalk |
| title_sort | tdp 43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting r loop and 5hmc crosstalk |
| topic | CP: Neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S221112472301673X |
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