Cells across the eukaryotic tree of life appear to rely on a remarkably ancient system for switching genes on, while using a far more diverse set of molecular strategies to keep genes off, according to a comparative study from the Centre for Genomic Regulation (CRG) in Barcelona. Published in Nature Genetics, the research provides the broadest examination yet of chromatin regulation across distantly related eukaryotes, including organisms whose genome-control systems have rarely been investigated. The findings suggest that gene activation has remained broadly conserved for roughly two billion years, whereas gene repression has repeatedly evolved in response to the changing threats faced by different genomes.
Chromatin is the molecular framework that determines how DNA is packaged and interpreted inside a cell. Long strands of DNA are wrapped around proteins called histones, and chemical modifications attached to those histones help identify regions that should be read, paused or silenced. This system enables cells carrying the same genome to develop into radically different forms, such as neurons, liver cells, roots or leaves. When chromatin regulation fails, genes can become active or inactive at the wrong time, contributing to conditions including cancer and other diseases.
The chemical marks involved in this process are thought to have been present in the Last Eukaryotic Common Ancestor, or LECA, a single-celled organism that lived approximately two billion years ago and gave rise to modern animals, plants, fungi and protists. Many of the enzymes that add or remove histone modifications are still shared across these lineages. Yet most detailed knowledge of how the system works has come from a small collection of laboratory organisms, including humans, mice, fruit flies, baker’s yeast and the model plant Arabidopsis thaliana. The new study extends that view to branches of the eukaryotic tree that have largely been missing from chromatin research.
“The cell’s instructions for activating genes are essentially the same in a human, a sea anemone and a soil amoeba,” says Arnau Sebé-Pedrós, an ICREA Research Professor at the CRG and senior author of the study. “But the instructions for silencing genes and other genomic elements like transposons have been continuously evolving since our last common eukaryotic ancestor. Different branches of life have developed different molecular toolkits to do the same thing.”
To make the comparison possible, the researchers developed iChIP2, an expanded version of a chromatin-profiling method. The technique uses molecular barcodes to label chromatin from multiple species and analyze the samples together in a single experiment. This design makes it possible to compare histone modifications under consistent experimental conditions while working with very small quantities of biological material. The approach is particularly valuable for organisms that are difficult to grow or that have not previously had their epigenetic states mapped.
The team used iChIP2 to examine twelve histone modifications across twelve phylogenetically diverse species. The collection included the soil amoeba Acanthamoeba castellanii, the freshwater amoeba Naegleria gruberi, the ciliate Tetrahymena thermophila, the chytrid fungus Spizellomyces punctatus, baker’s yeast Saccharomyces cerevisiae, the ichthyosporean Creolimax fragrantissima, the marine predator Bigelowiella natans, the alga Guillardia theta, the plants Arabidopsis thaliana and Physcomitrium patens, the social amoeba Dictyostelium discoideum and the sea anemone Nematostella vectensis. Several of these species had never undergone detailed chromatin mapping.
Across the organisms, active genes carried a highly similar chromatin signature. Histone modifications associated with transcription tended to cluster around the beginning of a gene and extend across the gene body, indicating that the basic molecular language for gene activation has remained stable since early eukaryotic evolution. Repressed genes, however, displayed strikingly different patterns. Some species used separate modifications to silence transposable elements and inactive genes, while others combined multiple repressive marks on the same stretches of DNA. In Acanthamoeba, a modification commonly associated with active genes in animals appeared to have been repurposed for gene repression.
The researchers propose that much of this diversity reflects an evolutionary struggle between host genomes and parasitic genetic material. Transposable elements, often called jumping genes, can copy or move themselves to new positions in a genome, potentially disrupting genes or altering chromosome structure. Endogenized viruses and other mobile sequences can also persist within genetic material and evolve ways to escape cellular defenses. In humans, transposable-element-derived sequences make up approximately half of the genome. Because these elements differ between lineages, the systems used to suppress them may also have diverged.
“If a species loses its repressive mechanisms completely, it can’t tolerate parasitic elements like transposable elements or endogenized viruses,” Sebé-Pedrós says. “The result is that it’s no longer there. It’s dead.” Over hundreds of millions of years, this pressure may have produced a series of lineage-specific solutions, with chromatin marks and the enzymes that control them repeatedly adapted, combined or reassigned. Some mechanisms originally evolved to restrain mobile DNA may later have been recruited to regulate ordinary genes and other genomic regions.
The results arrive as projects such as the Earth BioGenome Project and the Wellcome Sanger Institute’s Tree of Life programme accelerate the sequencing of species from across the planet. Genome sequences reveal an organism’s genetic parts list, but they do not fully explain when those genes are active or how potentially harmful sequences are controlled. By enabling chromatin comparisons across unfamiliar species, iChIP2 could help add this regulatory layer to future biodiversity studies. The researchers say that examining more branches of life may reveal additional strategies for controlling DNA—and clarify how the molecular systems underlying health, disease and genome stability evolved.
Subject of Research: Comparative evolution of chromatin regulation and histone modifications across diverse eukaryotic species.
Article Title: Diversity and evolution of chromatin regulatory states across eukaryotes
Web References: https://doi.org/10.1038/s41588-026-02672-1
References: Nature Genetics, “Diversity and evolution of chromatin regulatory states across eukaryotes,” DOI: 10.1038/s41588-026-02672-1.
Image Credits: Sean Montgomery/Centro de Regulación Genómica
Keywords: chromatin, histone modifications, gene regulation, epigenetics, eukaryotes, transposable elements, endogenized viruses, genome evolution, iChIP2, comparative genomics
