Photo credit: www.sciencedaily.com

Unveiling the Secrets of the “Dark Side” of the Genome

The enigmatic realm of the “dark side of the genome,” known scientifically as heterochromatin, is gaining attention as researchers begin to explore its pivotal role in cellular health. Comprising nearly half of our genetic material, this understudied fraction of DNA has remained largely mysterious for over five decades. Recent findings suggest that the proper functioning of heterochromatin is essential for keeping cells in a healthy condition.

Within heterochromatin lies an array of potentially harmful DNA segments referred to as “transposable elements” (TEs). Under normal circumstances, these elements remain dormant, nestled within the protective confines of heterochromatin. However, various pathological states can trigger their activation, causing TEs to “jump” into functional regions of our genome.

Interestingly, while TEs can occasionally facilitate beneficial genetic adaptations—such as the development of specific genes for immune response and placental evolution—they can also pose serious health risks. Emerging research has implicated the deterioration of heterochromatin in a host of health issues, including aging, the early stages of malignant transformation, cancer, and autoimmune disorders.

“Heterochromatin acts as a prison for transposable elements,” states Dr. Anjana Rao, a professor at the La Jolla Institute for Immunology and lead author of a recent study published in Nature Structural & Molecular Biology. Alongside collaborators, she points out that when heterochromatin’s silencing function diminishes, not only do TEs break free, but cellular health also diminishes.

The recent research highlights an ingenious cellular strategy to safeguard against the erratic activity of TEs. The study’s authors discovered that cells employ an extensive network of proteins to inhibit TE activities and maintain cellular integrity.

“Reactivated transposable elements can result in significant genomic instability,” explains Dr. Hugo Sepulveda, a co-first author of the study. He emphasizes that even a slight increase in the expression of these elements can disrupt the function of nearby genes, contributing to various diseases such as cellular senescence, the aging process, autoimmune conditions, and multiple cancer types.

Mechanisms of Control: O-GlcNAc Transferase (OGT)

Central to the regulation of transposable elements is O-GlcNAc transferase (OGT), an enzyme involved in numerous critical cellular processes. The latest research identifies OGT as a key player in repressing TE activity and ensuring smooth gene expression.

In this study, researchers built upon previous findings that demonstrated OGT’s interaction with TET enzymes, which were identified by Dr. Rao’s lab in 2009. TET proteins are integral to the proper modification of DNA within our cells and help activate necessary transcriptional patterns.

Through a vital cycle of DNA modifications, TET proteins facilitate DNA demethylation, a process that alters molecular markers attached to DNA. Two prevalent DNA markers—5mC and 5hmC—serve roles in gene silencing and activation respectively. The modulation of these markers by TET proteins grants cells the responsiveness needed to adapt to environmental challenges and health threats.

While DNA demethylation is crucial, cells also require balance. TET activity must be selectively mediated to prevent the simultaneous activation of all genes. The new findings reveal that OGT plays a protective role by regulating TET enzyme activity, particularly in suppressing the unnecessary expression of TEs.

The Future of Research on Health and Disease

This groundbreaking discovery illustrates how non-coding regions within our genome can become active when the TET function is disrupted. Understanding the partnership between OGT and TET informs us about how these proteins and their respective modifications could drastically influence cellular health.

“We often regard transposable elements as inactive, yet the reality is that substantial efforts are needed to maintain their silence,” notes Dr. Sepulveda.

Furthermore, this research has potential implications for the development of new therapeutic strategies. While numerous genes associated with cancer have been identified, managing their expression remains complex. The newfound insights suggest that targeting TE activity in cancer cells through the OGT-TET pathway may present novel therapeutic opportunities.

“We aim to harness this knowledge and could possibly control TE activity through OGT and TET,” Dr. Sepulveda remarks.

Dr. Rao reiterates the urgent need for further investigations into how OGT regulates DNA modifications and TE expression, especially in the context of autoimmune diseases, cancers, and other health conditions.

This research received funding from the National Institutes of Health (grants R35 CA210043, NIGMS R35GM147554), an NHMRC Investigator Grant (GNT1173711), the Mater Foundation, the Pew Latin-American Fellows Program from The Pew Charitable Trusts, a fellowship from the California Institute for Regenerative Medicine, and the UCSD Graduate Training Program in Cellular and Molecular Pharmacology (through the institutional training grant NIH NIGMS T32 GM007752).

Source
www.sciencedaily.com