HKU Researchers Uncover Alternative Gene Regulation in Organisms Lacking DNA Methylation

Researchers at The University of Hong Kong (HKU) School of Biological Sciences have identified an alternative mechanism by which eukaryotic cells regulate gene activity. This discovery is particularly significant for understanding organisms that have lost a primary gene-regulatory system during evolution, with the microscopic roundworm C. elegans serving as the study's model. The findings were published in Nature Communications.

Cells maintain proper function by controlling gene expression. This process is influenced by epigenetic mechanisms, which modify gene activity without altering the DNA sequence itself. A common epigenetic mechanism involves DNA methylation, where a methyl group is added to cytosine (forming 5-methylcytosine or 5mC) to signal gene deactivation.

While 5mC is crucial in many species, some organisms, such as C. elegans, have independently lost DNA methylation.

The method by which these organisms maintain gene regulation without 5mC was previously unclear.

The HKU team, led by Dr. Emily Hok Ning Tsui, Professor Karen Wing Yee Yuen, and Professor Chaogu Zheng, demonstrated that cells can shift to an alternative epigenetic mechanism when DNA methylation is absent. Instead of relying on DNA-based chemical labels, these cells utilize various histone modifications. Histones are proteins around which DNA is wrapped within a cell.

The research specifically focused on the protein MBD-2 (methyl-CpG-binding domain protein 2). In many animals, MBD-2 recognizes 5mC-marked DNA and assists in gene silencing or activation. Surprisingly, C. elegans, despite lacking DNA methylation, still requires its version of MBD-2.

The team found that in C. elegans, MBD-2 does not interpret DNA methylation signals. Instead, it associates with specific repressive histone marks, particularly H3K27me3, which is linked to gene silencing.

Deletion of MBD-2 in C. elegans resulted in infertility and significant physical defects, along with widespread gene dysregulation. This indicates that MBD-2 is a critical regulator of gene activity even in the absence of DNA methylation.

These findings suggest that epigenetic regulation is highly adaptable.

When a primary gene-control system is lost, organisms can adapt to read different signals and maintain precise control over gene expression.

Professor Karen Yuen noted that the study highlights the functional conservation of the NuRD complex and the plasticity of epigenetic mechanisms in eukaryotes.

This research contributes to a better understanding of human diseases characterized by aberrant gene regulation, such as cancers, neurological disorders, and autoimmune conditions. Insights into how epigenetic mechanisms compensate for one another may facilitate the development of new therapeutic strategies.