TDP-43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting R-loop and 5hmC crosstalk

Hou, Yingzi; Li, Yangping; Xiang, Jian-Feng; Tilahun, Kedamawit; Jiang, Jie; Corces, Victor G.; Yao, Bing

doi:10.1016/j.celrep.2023.113662

Cell Reports

2024

DOI: 10.1016/j.celrep.2023.113662

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TDP-43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting R-loop and 5hmC crosstalk

Yingzi Hou,

Yangping Li,

Jian-Feng Xiang

et al.

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2024

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Cited by 3 publications

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Evolution of Repetitive Elements, Their Roles in Homeostasis and Human Disease, and Potential Therapeutic Applications

Snowbarger,

Koganti,

Spruck

2024

Biomolecules

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Repeating sequences of DNA, or repetitive elements (REs), are common features across both prokaryotic and eukaryotic genomes. Unlike many of their protein-coding counterparts, the functions of REs in host cells remained largely unknown and have often been overlooked. While there is still more to learn about their functions, REs are now recognized to play significant roles in both beneficial and pathological processes in their hosts at the cellular and organismal levels. Therefore, in this review, we discuss the various types of REs and review what is known about their evolution. In addition, we aim to classify general mechanisms by which REs promote processes that are variously beneficial and harmful to host cells/organisms. Finally, we address the emerging role of REs in cancer, aging, and neurological disorders and provide insights into how RE modulation could provide new therapeutic benefits for these specific conditions.

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Evolution of Repetitive Elements, Their Roles in Homeostasis and Human Disease, and Potential Therapeutic Applications

Snowbarger,

Koganti,

Spruck

2024

Biomolecules

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Beyond the Synapse: FMR1 and FMRP Molecular Mechanisms in the Nucleus

Hansen,

Dischler,

Dias

2024

IJMS

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FMR1 (Fragile X messenger ribonucleoprotein 1), located on the X-chromosome, encodes the multi-functional FMR1 protein (FMRP), critical to brain development and function. Trinucleotide CGG repeat expansions at this locus cause a range of neurological disorders, collectively referred to as Fragile X-related conditions. The most well-known of these is Fragile X syndrome, a neurodevelopmental disorder associated with syndromic facial features, autism, intellectual disabilities, and seizures. However, CGG expansions of different sizes also confer a risk of neuropsychiatric and neurodegenerative disorders throughout the lifespan, through distinct molecular mechanisms. Although Fragile X syndrome is associated with downstream synaptic deficits and neuronal hyperexcitability, work in the past decade has demonstrated that both the causative FMR1 trinucleotide repeat expansion and FMRP itself play important roles in nuclear function and regulation, including non-canonical nucleic acid structure formation and chromatin dynamics. These effects are critical to cellular pathophysiology, although the full extent of their contribution to clinical phenotypes is only just emerging. Here, we present a focused review on some of the nuclear consequences of FMR1/FMRP dysregulation, including parallels in other repeat expansion disorders, ranging from studies in model systems to human cells and tissues.

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Progress in the role and mechanism of TDP-43

2024

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Background: TAR DNA-binding protein 43 kDa (TDP-43) has been shown to play an important role in the development of neurodegenerative diseases, but the mechanism is still under study. Methods: By utilizing “TDP43”, “disease”, and “mechanism” as the keywords, 200 related studies were retrieved and downloaded from Pubmed database, including 60 articles. We summarized the progress in understanding TDP-43 mechanism over the past two years, focusing on disease systems and classification of the upstream and downstream, including connection, improvement, and formation. Results: TDP-43, when abnormally aggregated, phosphorylated, or mislocalized, plays a key pathological role in neurodegenerative diseases. Additionally, its impact on normal reproductive cell formation, development, quantity, and activity, as well as insulin secretion and the activation of intestinal epithelial cell necrosis, should not be overlooked. Mechanistically, we identified a relationship between the expression of upstream factors, including Enterovirus D68 (EV-D68), Heterogeneous Nuclear Ribonucleoprotein D (HNRNPD or AUF1), Endoplasmic Reticulum Protein 57 (ERp57), and Progranulin (PGRN), and downstream factors such as Meiotic Recombination Protein Spo11 (Spo11), AMP-Activated Protein Kinase (AMPK), Double-Strand-Break Repair Protein Rad21 Homolog (Rad21L), IκB Kinase (IKK), and TDP-43. Conclusion: TDP-43 plays a pathological role in neurodegeneration, of which, the expression is related to phosphorylation, EV-d68, and HNRNPD.

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TDP-43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting R-loop and 5hmC crosstalk

Cited by 3 publications

References 116 publications

Evolution of Repetitive Elements, Their Roles in Homeostasis and Human Disease, and Potential Therapeutic Applications

Evolution of Repetitive Elements, Their Roles in Homeostasis and Human Disease, and Potential Therapeutic Applications

Beyond the Synapse: FMR1 and FMRP Molecular Mechanisms in the Nucleus

Progress in the role and mechanism of TDP-43

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