- The revolutionary method, named METALoci, developed by Dr Marc A. Marti-Renom (CNAG, CRG) and Dr Juan Antonio Rodríguez (CNAG), has enabled the discovery of new genomic factors involved in sex differentiation, including a previously unknown non-coding regulatory region at the Fgf9 locus and the Meis1 and Meis2 genes.

- The novel computational framework identifies 3D regulatory hubs and produces detailed gene regulation maps for different cell types, opening new possibilities for genome engineering and for precise gene modulation in living organisms, a major step forward for developing new therapeutic strategies. 
- The study, led by the Centre Nacional d’Anàlisi Genòmica (CNAG) in collaboration with the Centro Andaluz de Biología del Desarrollo (CABD, Spain), the Max Delbrük Center for Molecular Medicine (MDC, Germany), and the Duke University Medical Center (USA), has been published today in Nature Structural & Molecular Biology.
 
 
February 24th, 2026. In mammals, whether an individual develops ovaries or testes is a matter of genetics. Before this process begins, a single key gene on the Y chromosome sets the path: acting like a master switch, the protein coding gene Sry flips on the Sox9 “box” and initiates the cascade that leads to testis development. In its absence, the pathway proceeds by default, guiding the formation of ovaries in individuals with two X chromosomes. Although this basis has been known since the 20th century, scientists are still asking how epigenetic mechanisms determine when and where these genes act, and what role 3D genome organisation plays in this vital process at the heart of the species’ reproductive system.
 
 
Now, researchers Dr Marc A. Marti-Renom from the Centre Nacional d’Anàlisi Genòmica and the Center for Genomic Regulation (CNAG, CRG, Spain), Dr Darío G. Lupiáñez from the Centro Andaluz de Biología del Desarrollo (CABD, Spain) and Dr Blanche Capel from the Duke University Medical Center (DUKE, USA), provide new answers to these questions in their latest study published in Nature Structural & Molecular Biology, shedding light on the mechanisms involved in sex determination in mammals. 
 
 
One of the first challenges was obtaining the right material: the tiny populations of gonadal cells, which represent the sexual organs before sex determination, compared with the cells after this process. Surprisingly, even using Hi-C and ChIP-seq techniques, the overall 3D chromatin structure showed only little differences, suggesting that the most critical regulatory events occur before the gonads differentiate into ovaries or testes. 
 
 
This result marked the beginning of the second challenge, which was tackled by Dr Marc A. Marti-Renom (CNAG, CRG) and Juan Antonio Rodríguez (CNAG) through the development of METALoci, a powerful new computational framework whose name captures its ambition: META (meaning many) and loci (the specific regions of the genome), bringing together a comprehensive and unified view of multiple genomic sites that had remained hidden until now. By revealing how these regions interact in three dimensions, METALoci not only deepens our understanding of sex determination, but also provides a versatile tool with applications far beyond this biological process, laying the foundation for more precise genome engineering and for the modification of gene expression in living organisms.
 
 
“METALoci is a game-changer in genome research,” says Dr Marc A. Marti-Renom, ICREA Professor, the Structural Genomics Group Leader at CNAG and CRG, and corresponding author of the study. “This new computational method goes far beyond traditional 3D genome mapping. For the first time, it provides a predictive computational tool that allow us to uncover non-coding regulatory regions and reconstruct the three-dimensional hubs that coordinate gene expression. This opens the door to understanding the hidden layers of genome regulation that drive development, cell identity, and disease.” 
 
 
Decoding how the same gene plays different roles in different tissues
 
By integrating Hi-C and epigenetic data, METALoci reconstructs 3D regulatory hubs, uncovering previously unknown interactions that guide sex determination. Using this geostatistics-inspired method, researchers identified a novel regulatory region controlling Fgf9, a key gene that acts downstream of Sry to activate Sox9 and trigger testis development, as well as a previously unknown role for Meis1 and Meis2 genes during sex diffentiation. Together, these findings provide important insights and represent an important step towards understanding Differences of Sex Development (DSD), a group of conditions that can affect reproductive capacity in humans.
 
 
Beyond discovering this new rewiring regulatory mechanisms, METALoci also provides a powerful approach to understand how the same gene can play distinct roles in different tissues. For example, deletion of the Fgf9 gonadal regulatory region in mice not only caused a male-to-female sex reversal but did not interfere with the role of the gene during lung development, as it rescued the lung perinatal lethality typically associated with complete Fgf9 inactivation. This demonstrates how METALoci can reveal how the same gene behaves differently across tissues, uncovering functions that would not be detected with conventional approaches.
 
 
 
 
REFERENCE ARTICLE
Mota-Gómez, Irene, et al. ‘Chromatin Spatial Analysis by METALoci Unveils Sex-Determining 3D Regulatory Hubs’. Nature Structural & Molecular Biology, Feb. 2026, pp. 1–13. www.nature.com, https://doi.org/10.1038/s41594-026-01749-z.