In the complex journey of decoding the mysteries of the brain, TDP-43 becomes a key figure, leading to the internal work of the cellular landscape. TDP-43’s failure is well known for its critical role in managing RNA information in cells and maintaining the stability of genetic material, and is closely linked to the mysterious emergence of neurological conditions such as ALS and dementia. When TDP-43 stumbles, it triggers the domino effect of failure, from misleading stress responses in cells to errors in units of energy generated in distress and genetic information, laying the foundation for the gradual loss of neuronal function. The story of TDP-43 is not only one of the stories of decline, but also provides a glimpse of the fine balance that maintains the health of the brain. When the scientists delved into this terrain, they discovered molecular markers (R-loops and 5hmc), which, when misled by the lack of TDP-43, revealed potential neurodegeneration pathways and revealed a complex interaction network, thus maintaining our cognitive abilities.
The team at Emory University is led by Dr. Bing Yao, including Dr. Yingzi Hou, Dr. Yangping Li, Dr. Jian-Feng Xiang, Kedamawit Tilahun, Dr. Jie Jiang and Professor Victor Corces take an important step by revealing TDP -43’s key role is to reveal the complex nature of neurodegenerative diseases. This protein is involved in genetic information within cells and has been associated with brain diseases such as Alzheimer’s disease and ALS.
TDP-43 plays a crucial role in cells, helping to manage and protect genetic information and participate in the process of converting genetic material into functional cellular components. Its accumulation outside the nucleus is associated with several diseases in the brain, leading to cell dysfunction and death.
Dr. Bing Yao highlighted the significant impact of TDP-43 on cell health, noting that “the chronic lack of TDP-43 affects the nearby and distance genetic behavior by altering the interaction between R-loops of the genetic material and 5HMCs in enhanced gene behavior When disturbed, this complex balance leads to significant changes in cellular behavior, which can lead to the development of brain disease.
The team carefully demonstrated how the prolonged deletion of TDP-43 leads to widespread destruction of the cellular genetic landscape. By affecting the balance between R loops, the structures formed during reading genetic information that may affect gene regulation and 5HMCs, which are modifications to the genetic code involved in activating gene expression, TDP-43 lacks disrupts normal cellular function. This interference extends to enhancers, which is essential for controlling long-distance gene expression, thus affecting the genes responsible for cell growth and response to genetic damage.
A key finding is that the family of transposable elements (TE) associated with neurodegeneration is activated due to changes in the balance of R loops and 5HMCs at the TE genomic loci. These elements form an important part of the human genome, have the ability to move through genetic material, and their activation is a marker of genetic instability, often associated with disease states.
Dr. Yao further highlighted the broader implications of their findings, noting that “our data provides a comprehensive interaction of the various roles of TDP-43 in maintaining the R-loops and 5hmc balance.” In-depth understanding emphasizes its potential as a key factor in the onset of neurodegenerative disease. The implications of this study are profound and provide new perspectives on the molecular origins of neurodegenerative diseases. By elucidating the role of TDP-43 in gene and TE regulation, this study lays the foundation for future research strategies that can reduce the impact of TDP-43 dysfunction and thus provide people affected by these challenging conditions hope.
Journal Reference
Yingzi Hou, Yangping Li, Jian-Feng Xiang, Kedamawit Tilahun, Jie Jiang, Victor G. Corces, Bing Yao, “Chronic defects in TDP-43 cause dysregulation of metastatic elements and gene expression and by affecting R-looloop and 5HMC Crosstalk Effects of Cell Report, January 23, 2024. doi: https://doi.org/10.1016/j.celrep.2023.113662
About the Author
Dr. Bing Yao Bing Yao I am an associate professor of human genetics and my long-term research interest is to understand the critical role of epigenetic regulation in mammalian neurodevelopment and the potential for dysregulation of these processes to cause neuropathology. I have extensive backgrounds in genetics, epigenetics, cell biology, biochemistry, molecular biology, and bioinformatics. Since opening my lab in the fall of 2017, I have established a multifaceted research program to address fundamental problems at different levels of neuronal literacy. Ongoing projects in my lab include i) typical epigenetic mechanisms such as DNA modification, ii) a novel DNA: an RNA hybrid structure called “R-loops” and III) a unique class of Regulatory RNA, with a circular structure called CIRCRNA, is a CIRCRNA, a CIRCRNA, broadly speaking, considered an “epigenetic regulator.” We aim to elucidate their coordinated function in neurodevelopment and how dysregulation of these processes leads to brain diseases such as Alzheimer’s disease (AD). Our work integrates a variety of approaches including genome-wide high-throughput epigenomics and transcriptome analysis, CRISPR-CAS9 gene editing and engineering, and cellular and molecular biology. We are using next-generation long-read sequencing, single-cell epigenomics, and spatial transcriptome technologies to enhance our study resolution. We have established mouse models of various diseases, acquired human post-brain, and developed human IPSC-derived 2D neurons and 3D mini brain organs to study these mechanisms in vitro and in vivo.
Dr. Yingzi Hou I joined Dr. Bing Yao’s lab as a postdoctoral fellow. I am excited to learn more about epigenetic mechanisms in brain development and brain diseases and are investigating the role of R-ring in nervous system and related diseases.
Yangping Li, Ph.D. I joined Dr. Bing Yao’s lab and became a postdoctoral researcher. I am very interested in using comprehensive computational analysis to better understand the epigenetic mechanisms of mammalian brain development and neurodegenerative diseases.
