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

A groundbreaking study recently published in Stem Cell Reports by researchers at the University of Michigan delves into the complex biochemical signals that govern the differentiation of stem cells into retinal cells. This research sheds new light on the epigenetic and epitranscriptomic mechanisms that refine how cells read their genetic blueprints to specialize, offering promising insights for regenerative medicine, particularly in therapies targeting retinal diseases.

At the core of this investigation lies a protein called METTL3, known for its role in adding methyl groups—a type of chemical modification—to RNA molecules. Such methylation is a critical regulatory mechanism that influences RNA stability and translation efficiency, directly impacting protein production. Previous studies have implicated RNA methylation in various diseases including diabetes and cancer, but its specific role in directing stem cell fate toward retinal development was unexplored until now.

The team utilized advanced genetic tools to either eliminate METTL3 or engineer versions of the protein incapable of RNA methylation. Intriguingly, the absence or functional impairment of METTL3 dramatically hindered the formation of retinal cells from stem cells. This dependency highlights the essential nuclear activity of METTL3 during retinal lineage commitment, suggesting that RNA methylation plays a pivotal part within the nucleus to orchestrate gene expression tailored for retinal development.

To map the precise RNA targets affected by METTL3, the researchers employed an innovative technique named GLORI (Global RNA Interactome Mapping), enabling high-resolution identification of methylation sites across the stem cell transcriptome. Through this mapping, they pinpointed key regulatory modifications on RNA molecules involved in retinal differentiation pathways, notably on Six3, a gene encoding a critical transcription factor that drives the stem cell-to-retina developmental switch.

Further experimentation demonstrated that these RNA methylations modulate the stability of Six3 transcripts. By deploying an RNA-specific CRISPR editing system, modifications situated at the 3’ terminus of Six3 RNA were found to be especially influential in controlling transcript stability. This fine-tuning directly affects the gene’s protein output, reinforcing the concept that RNA chemical modifications serve as sophisticated regulators of gene expression during retinal cell formation.

Beyond METTL3, the study also identified the Ythdf family of genes as essential mediators of this epitranscriptomic regulation. Inhibiting the expression of these genes mimicked the retinal development blockade observed with METTL3 loss, suggesting that the Ythdf proteins function as readers of methylated RNA, translating chemical marks into functional outcomes that promote retinal cell differentiation.

This research pioneers the exploration of RNA epigenetics in the context of retinal development, unraveling a previously unappreciated layer of gene regulation. By uncoupling chromatin accessibility from transcriptional output, METTL3’s RNA methylation activity delicately choreographs the progression from multipotent stem cells to specialized retinal tissue. These findings pave the way for new therapeutic avenues in retinal disease, where defective cellular differentiation or degeneration remains a major clinical challenge.

Intriguingly, the team uncovered that METTL3 modulates RNA without inducing changes in chromatin structure—an unexpected observation that challenges prevailing paradigms linking epigenetic modifications on chromatin with transcriptional control. This decoupling phenomenon suggests a unique intracellular mechanism by which RNA methylation exerts selective control over developmental gene expression programs without altering DNA accessibility.

Moreover, the researchers are now investigating how metabolic conditions, such as elevated glucose levels common in diabetes, influence RNA methylation patterns. Given the retina’s vulnerability to metabolic stress and the known damage caused by diabetes, understanding the interplay between metabolic states and RNA epigenetics could unlock vital clues to preventing or ameliorating diabetic retinopathy and other retinal disorders.

The implications of this study extend beyond developmental biology, offering a molecular foundation for stem cell-based regenerative therapies and precision drug screening for retinal diseases. By targeting the enzymes and pathways governing RNA methylation, future interventions may enhance the efficiency of generating retinal cells in vitro and develop strategies to maintain retinal health in disease states.

In summary, the University of Michigan study represents a landmark in elucidating how chemical modifications on RNA function as master regulators in stem cell differentiation toward retinal cells. The elucidation of METTL3’s role and its downstream effectors not only deepens our understanding of retinal development but also spotlights RNA epigenetics as a promising frontier in regenerative medicine and ophthalmic research.

Subject of Research: Cells

Article Title: METTL3 Uncouples Chromatin Accessibility from Transcription during Retinal Development

News Publication Date: 23-Oct-2025

Web References:
https://doi.org/10.1016/j.stemcr.2025.102690

References:
“METTL3 Uncouples Chromatin Accessibility from Transcription during Retinal Development,” Stem Cell Reports. DOI: 10.1016/j.stemcr.2025.102690

Keywords: Health and medicine, Life sciences

Pregnancy is infamously characterized by its unpredictable duration. Although the average pregnancy lasts approximately 40 weeks, actual gestation periods can vary widely, ranging from 38 to 42 weeks. The mechanisms governing this intricate timeline have remained shrouded in mystery. However, the UCSF team, through a meticulous examination of molecular activities in the uterus, has discovered that a specific set of molecules presumably initiates a countdown soon after conception.

The pivotal finding stems from the study of a protein known as KDM6B, which regulates the expression of a multitude of genes involved in the pregnancy process. The researchers initially hypothesized that KDM6B would activate genes in the uterine epithelial cells, which are responsible for producing hormones that trigger labor. However, their exploration led them instead to focus on fibroblasts, the structural cells within the uterus that had not previously been linked to labor regulation.

The study indicates that immediately following fertilization, there is an increase in methyl groups on the histones associated with certain genes in the uterine fibroblasts. This methylation keeps these genes dormant, ensuring that the uterus can maintain a supportive environment for the developing fetus during the early stages of pregnancy. As pregnancy progresses, the methylation marks on these histones slowly diminish, acting as a built-in molecular timer. Once the methylation levels reach a specific threshold, the genes governing labor become active, signaling the onset of childbirth.

When KDM6B was inhibited in the mouse model, pregnancies were found to be inexplicably prolonged. This alteration in the molecular landscape resulted in an increased level of histone methylation, which in turn raised the bar for the activation of labor-related genes. Consequently, the animals experienced delayed labor, underscoring the critical role of KDM6B in the timing of childbirth.

The implications of these findings could extend to human pregnancies, prompting critical questions about whether similar mechanisms operate in human gestation. If the molecular timer identified maintains relevance in humans, it could pioneer new avenues for predicting and potentially managing preterm births. For instance, women who might naturally possess lower levels of histone methylation at the outset of pregnancy could face a heightened risk of early labor due to the accelerated activation of genes that induce childbirth.

The research team emphasizes that their findings bridge a significant gap in understanding the temporal dynamics of labor initiation. Traditional studies have mainly centered on the immediate biological changes occurring as labor approaches. In contrast, the UCSF research urges a renewed focus on the initial stages of pregnancy, where disturbances in gene regulation may harbor wider implications for pregnancy outcomes.

Our understanding of who is at risk of preterm birth could be transformed if KDM6B and the molecular timer mechanisms are validated in human subjects. Medical practitioners may develop screening tests to assess methylation levels in expectant mothers, allowing for early identification of those at higher risk for preterm labor. This would represent a pivotal shift in obstetrics, with the potential to implement proactive interventions before complications arise.

Furthermore, the team’s insights into the role of uterine fibroblasts in regulating labor are particularly significant. While traditionally overlooked, these cells may prove to be key players in understanding the biological mechanisms that govern not just pregnancy duration but overall reproductive health. The multifaceted interactions between various cell types reveal an intricate network of signaling pathways that have previously remained underappreciated in reproductive biology.

As the research unfolds, its implications could be profound, prompting a reevaluation of existing approaches to managing pregnancy complications. The study calls for further investigations, potentially leading to pharmaceutical advancements or therapeutic strategies aimed at safeguarding the health of mothers and their newborns.

In summary, the recent findings from UCSF provide critical insights into the biological clock of pregnancy, underlying the importance of molecular mechanisms in determining labor timing. As researchers continue to delve deeper into the fundamental biology of reproduction, they may uncover novel strategies to provide better care for expectant mothers and reduce the risks associated with preterm births.

These findings mark a promising step forward in understanding one of reproductive medicine’s most pressing challenges: how to ensure that pregnancies reach a safe conclusion while minimizing the risk of premature delivery. This research paves the way for innovative approaches to maternal health and newborn care, setting the stage for future breakthroughs in obstetric practices.

Subject of Research: Molecular mechanisms of pregnancy length regulation
Article Title: Discovery of a Molecular Timer in Pregnancy Offers New Insights into Preterm Birth
News Publication Date: January 21, 2023
Web References: UCSF Health
References: Erlebacher, A., et al. (2023). Cell
Image Credits: UCSF Health

Keywords: Preterm birth, molecular timer, KDM6B, histone methylation, fibroblasts, gene regulation, pregnancy duration, obstetrics.