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METALoci, a novel computational framework that reveals 3D genomic mechanisms of sex determination in mammals
published on 25/03/2026
The revolutionary method 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 Centro Andaluz de Biología del Desarrollo (CABD, Spain) and the Max Delbrück Center for Molecular Medicine (MDC, Germany) in collaboration with the Centre Nacional d’Anàlisi Genòmica (CNAG) and the Duke University Medical Center (USA), has been published in Nature Structural & Molecular Biology.
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 initiates the cascade that leads to testis development. In its absence, the pathway proceeds to 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. Darío G. Lupiáñez from the Centro Andaluz de Biología del Desarrollo (CABD, Spain), Dr Marc A. Marti-Renom from the Centre Nacional d’Anàlisi Genòmica and the Center for Genomic Regulation (CNAG-CRG, 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 that initiates sex determination, before and after this process takes place. To address this, the Lupiáñez (CABD) and Capel (Duke) labs employed a combination of known genetic markers to isolate these cell populations. The further application of Hi-C, a technique to investigate 3D chromatin structure, revealed only minor differences during this process. This result was surprising, as it contrasted with the prominent changes in cell identity and gene expression that are characteristic of sex determination.
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 underlie sex determination. Using this geostatistics-inspired method, researchers identified a regulatory region controlling Fgf9, a key gene that acts downstream of Sry to trigger testis development, as well as a previously unknown role for Meis1 and Meis2 genes during sex differentiation. 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.
“The discovery of novel regulators of sex determination is particularly exciting, given that only a small number have been identified in recent decades,” say Irene Mota-Gómez and Darío Lupiáñez, researchers at the CABD and first and corresponding authors of the study, respectively. “It also highlights how new genomic tools, such as METALoci, can uncover genes that traditional approaches may have overlooked.”
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 caused male-to-female sex reversal but did not interfere with the role of the gene during lung development, as it rescued the 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.
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