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Transposable Elements: The DNA Jumpers that Shape Gene Regulation

Explore how jumping genes influence gene activity and immune responses.

Liangxi Wang, Tiegh Taylor, Kumaragurubaran Rathnakumar, Nadiya Khyzha, Minggao Liang, Azad Alizada, Laura F Campitelli, Sara E Pour, Zain M Patel, Lina Antounians, Ian C Tobias, Timothy Hughes, Sushmita Roy, Jennifer A Mitchell, Jason E Fish, Michael D Wilson

― 5 min read


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Table of Contents

Transposable Elements (TEs) are sequences of DNA that can move around within the genome. Think of them as the "jumping genes" of the cellular world. They can insert themselves into new locations, which might lead to changes in how genes are turned on or off. This movement and insertion can create new regulatory elements that affect gene expression, which is how cells control which proteins are made.

The Role of TEs in Gene Regulation

TEs are not just random pieces of DNA; they serve a vital purpose in shaping how genes respond to various signals. They can act as sources of new regulatory elements that help control nearby genes. This is important for many biological processes, including development, response to environmental changes, and even how our immune system works.

Transcription Factor Interactions

To understand how TEs affect gene regulation, scientists look at how Transcription Factors (TFs) bind to these elements. TFs are proteins that control the rate of gene expression by binding to specific DNA sequences. Identifying which TFs interact with TEs and under what conditions is a complex task that requires various experimental techniques.

Importance of Experimental Techniques

Using methods like chromatin immunoprecipitation followed by sequencing (ChIP-seq), researchers can unveil where TFs bind in the genome. Specifically, they're interested in TEs because these can provide unique binding sites for TFs, making them key players in regulating gene activity.

The NF-κB Pathway

One of the significant players in gene regulation is the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). This factor is crucial in our body’s immune response and inflammation. NF-κB activity is conserved across many species, meaning it has been maintained throughout evolution, which speaks to its importance.

NF-κB and Its Mechanism

In its inactive state, NF-κB proteins are kept in the cytoplasm by inhibitors. When certain signals, like inflammatory cytokines, are present, these inhibitors are degraded. This allows NF-κB to move into the nucleus, where it binds to regulatory elements near target genes that are involved in immune responses.

Variability Across Cell Types

The binding of NF-κB is not the same in all cell types. For example, in macrophages, it often binds to regions already occupied by another TF called SPI1. In aortic endothelial cells, the binding occurs in different areas, indicating that the cellular context greatly influences how NF-κB operates.

Cross-Species Comparisons

By comparing NF-κB binding across different species, scientists can reveal important regulatory principles that might be conserved throughout evolution. This reveals how the binding sites have changed, helping researchers understand the adaptability of gene regulation mechanisms.

TEs as Enhancers in Gene Regulation

TEs can also function as enhancers, which are sequences that increase the likelihood of transcription of particular genes. By enhancing the binding of NF-κB or other TFs, TEs can play an essential role in regulating gene expression during various biological processes.

The Relationship Between TEs and NF-κB

Recent studies have shown that some types of TEs are directly involved in NF-κB binding. These findings highlight how TEs can contribute to regulatory networks that control gene expression linked to immune responses.

Identifying TE Contributions

To identify the contributions of TEs to NF-κB binding areas, researchers examine the overlap between NF-κB target regions and known TE sequences. This helps determine how much TEs contribute to the regulatory landscape of different gene networks.

Evolutionary Aspects of TEs

The evolutionary history of these TEs is quite fascinating. Some TEs seem to have been around for a long time and are likely responsible for creating binding sites for TFs like NF-κB. Over time, as species evolved, the function and binding patterns of these TEs adapted to meet the needs of the organism.

TE Evolution and Adaptability

AN interesting area of study is how certain TEs have become specialized over time, allowing them to influence gene regulation. In some mammals, particular TE families have expanded significantly, raising questions about their role in specific adaptations or responses to environmental challenges.

The Bovine SINEs

In a distinctive case, certain TEs, particularly SINEs in bovines, have been found to contribute significantly to NF-κB binding sites. This expansion of TEs in bovine genomes is among the most notable examples of how a specific lineage of mammals might adapt to their unique environmental challenges.

TE-Mediated Enhancer Activity

Recent research has shown that TE-derived regions can act as enhancers that increase the expression of nearby genes, particularly those involved in immune responses. This enhancer activity can be vital in regulating gene expression during infection or inflammation.

The Functional Impact of TEs

The presence of TEs near critical genes can influence how those genes respond to external stimuli. By acting as enhancers, TEs can modify gene expression patterns, enhancing or dampening gene activity depending on the needs of the cell.

Collaborations Between TFs

It's important to note that TEs do not work alone. They often collaborate with other TFs to create a more complex regulatory network. For example, NF-κB may work together with AP-1 proteins in certain contexts to achieve effective gene regulation.

Looking to the Future

As we advance in our understanding of TEs and their contributions to gene regulation, we may uncover new avenues for therapeutic approaches. By manipulating these elements, it may be possible to fine-tune gene expression in response to diseases or developmental disorders.

Conclusion

Transposable elements are more than just "junk DNA." They play a crucial role in shaping the genome and influencing how genes are regulated. From their contributions to the NF-κB pathway to their role as enhancers, TEs are pivotal in the complex web of gene regulation. As we continue to explore the intricacies of these elements, we may find new insights into not only evolution but also innovation in genetic therapies.

So, the next time you hear about jumping genes, remember: they're not only hopping around in your DNA, but they might also be helping your genes have a little dance party when necessary!

Original Source

Title: Multi-species analysis of inflammatory response elements reveals ancient and lineage-specific contributions of transposable elements to NF-κB binding

Abstract: Transposable elements (TEs) provide a source of transcription factor binding sites that can rewire conserved gene regulatory networks. NF-{kappa}B is an evolutionary conserved transcription factor complex primarily involved in innate immunity and inflammation. The extent to which TEs have contributed to NF-{kappa}B responses during mammalian evolution is not well established. Here we performed a multi-species analysis of TEs bound by the NF-{kappa}B subunit RELA (also known as p65) in response to the proinflammatory cytokine TNF. By comparing RELA ChIP-seq data from TNF-stimulated primary aortic endothelial cells isolated from human, mouse and cow, we found that 55 TE subfamilies were associated with RELA bound regions. These RELA-bound transposons possess active epigenetic features and reside near TNF-responsive genes. A prominent example of lineage-specific contribution of transposons comes from the bovine SINE subfamilies Bov-tA1/2/3 which collectively contributed over 14,000 RELA bound regions in cow. By comparing RELA binding data across species, we also found several examples of RELA motif-bearing TEs that colonized the genome prior to the divergence of the three species and contributed to species-specific RELA binding. For example, we found human RELA bound MER81 instances were enriched for the interferon gamma pathway and demonstrated that one RELA bound MER81 element can control the TNF-induced expression of Interferon Gamma Receptor 2 (IFNGR2). Using ancestral reconstructions, we found that RELA containing MER81 instances rapidly decayed during early primate evolution (> 50 million years ago (MYA)) before stabilizing since the separation of Old World monkeys (< 50 MYA). Taken together, our results suggest ancient and lineage-specific transposon subfamilies contributed to mammalian NF-{kappa}B regulatory networks.

Authors: Liangxi Wang, Tiegh Taylor, Kumaragurubaran Rathnakumar, Nadiya Khyzha, Minggao Liang, Azad Alizada, Laura F Campitelli, Sara E Pour, Zain M Patel, Lina Antounians, Ian C Tobias, Timothy Hughes, Sushmita Roy, Jennifer A Mitchell, Jason E Fish, Michael D Wilson

Last Update: 2024-12-30 00:00:00

Language: English

Source URL: https://www.biorxiv.org/content/10.1101/2022.10.25.513724

Source PDF: https://www.biorxiv.org/content/10.1101/2022.10.25.513724.full.pdf

Licence: https://creativecommons.org/licenses/by/4.0/

Changes: This summary was created with assistance from AI and may have inaccuracies. For accurate information, please refer to the original source documents linked here.

Thank you to biorxiv for use of its open access interoperability.

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