For any organism to survive and thrive, its cells must tightly regulate when and where specific genes are active. New research by EMBL Heidelberg’s Noh Group, in collaboration with EMBL Australia, reveals key control sites that govern this process, particularly in relation to the activity of ancient viral sequences embedded in the genome to know how cells suppress genomic traces of ancient viruses.
| Date | September 18, 2024 |
| Source | European Molecular Biology Laboratory |
| Summary | Researchers have discovered key cellular control sites that regulate gene expression and prevent the activation of hidden genomic regions, including ancient viral sequences. |
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How Cells Suppress Genomic Traces of Ancient Viruses
For organisms, it’s essential to regulate when and where specific genes are expressed. Naturally occurring chemical modifications to histone proteins, which bind to DNA, are thought to play a significant role in this process. However, their direct influence on gene expression was uncertain. Through experimentation, researchers have demonstrated that certain histone sites serve as crucial control points, helping to prevent the accidental activation of genomic regions, including remnants of ancient viral sequences.
Our genomes are vast — a typical human cell contains over 6 billion units of DNA, or ‘base pairs.’ However, accessing the right information at the right time to perform specific functions presents a challenge. This is where epigenetic signatures come into play. Think of the genome as a book; epigenetic marks are like highlights on the pages or notes in the margins. But it’s unclear whether these marks direct the cell, telling it to “read this” or “ignore this,” or if they are simply remnants of past activity.
They focused on H3.3, a histone protein that binds to DNA and helps maintain its structure. H3.3 has sites on its tail, K9 and K27, that are often chemically modified. These modifications are believed to be epigenetic markers that regulate gene expression, but it has not been proven that they act as control sites.
The researchers experimentally altered these sites, creating a version of H3.3 that couldn’t be chemically modified. In terms of the book analogy, this created a page that couldn’t be marked, allowing the team to explore the consequences of losing these marks. By comparing the effects of losing modifications at each control site, they gained insights into their roles in gene regulation.
The scientists found that mutating these sites in mouse stem cells caused defects in differentiation, growth, and survival. It also led to the improper activation of genes across the genome, including immune-specific genes that shouldn’t be expressed in stem cells. This indicates that these sites normally help repress certain genes, preserving the stem cell state. The effects varied between the two control sites, highlighting their distinct roles in gene regulation.
Further analysis revealed that some activated regions are ancient viral remnants integrated into the genome, known as endogenous retroviruses (ERVs).
By mutating the K9 site in stem cells, the team found that many ‘cryptic’ enhancers, normally silenced, became active. “Repression of these unique genomic regions is essential for maintaining the cell’s gene expression balance,” Noh said. Activating these enhancers disrupts the gene regulatory network, impacting stem cell identity and function.
This study, conducted in collaboration with researchers from EMBL Australia, Washington University in St. Louis, and EMBL Heidelberg, was published in Nature Communications.
FAQ:
1. What are genomic traces?
Genomic traces are segments of DNA left behind by ancient viruses or other genetic elements that have been incorporated into the host organism’s genome over millions of years. These traces are often remnants of viral infections that integrated their genetic material into the host’s DNA.
2. How do viral sequences end up in the genome?
Some viruses, especially retroviruses, can integrate their genetic material into the host’s DNA during infection. If these integrations occur in reproductive cells (sperm or egg), the viral DNA can be passed on to future generations, becoming a permanent part of the host’s genome.