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Scientific advances<\/p>\n
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\u00a0The 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.<\/p>\n
The study, led by\u00a0the\u00a0Centro Andaluz de Biolog\u00eda del Desarrollo (CABD, Spain)\u00a0and the Max Delbr\u00fcck Center for Molecular Medicine (MDC, Germany)\u00a0in collaboration with\u00a0the\u00a0Centre Nacional d\u2019An\u00e0lisi Gen\u00f2mica (CNAG)\u00a0and the\u00a0Duke University Medical Center (USA), has been published in\u00a0Nature Structural & Molecular Biology<\/i>.<\/p>\n
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\u2011coding gene\u00a0Sry<\/i>\u00a0initiates the cascade that leads to testis development. In its absence, the pathway proceeds\u00a0to\u00a0the 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\u2019 reproductive system.<\/p>\n
Now, researchers\u00a0\u00a0Dr.\u00a0Dar\u00edo G. Lupi\u00e1\u00f1ez from the Centro Andaluz de Biolog\u00eda del Desarrollo (CABD, Spain),\u00a0Dr Marc A. Marti-Renom from the Centre Nacional d\u2019An\u00e0lisi Gen\u00f2mica and the Center for Genomic Regulation (CNAG-CRG, Spain)\u00a0and Dr Blanche Capel from the Duke University Medical Center (DUKE, USA), provide new answers to these questions in their latest study published in\u00a0Nature Structural & Molecular Biology<\/i>, shedding light on the mechanisms involved in sex determination in mammals.<\/p>\n
One of the first challenges was obtaining the right material: the tiny populations of gonadal cells\u00a0that initiates sex determination,\u00a0before\u00a0and\u00a0after this process\u00a0takes place.\u00a0To address this, the Lupi\u00e1\u00f1ez (CABD) and Capel (Duke) labs employed a combination of known genetic markers to isolate these cell populations. The further application of\u00a0Hi-C, a technique to investigate 3D chromatin structure,\u00a0revealed\u00a0only\u00a0minor 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.<\/p>\n
This\u00a0result\u00a0marked the beginning of the second challenge, which was tackled by Dr Marc A. Marti-Renom (CNAG-CRG) and Juan Antonio Rodr\u00edguez (CNAG) through the development of\u00a0METALoci<\/i>, 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,\u00a0METALoci<\/i>\u00a0not 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.<\/p>\n
\u201cMETALoci<\/i>\u00a0is a game-changer in genome research,\u201d says Dr Marc A. Marti-Renom, ICREA Professor, the Structural Genomics Group Leader at CNAG and CRG, and corresponding author of the study. \u201cThis 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.\u201d<\/p>\n
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Decoding how the same gene plays different roles in different tissues<\/u>
By integrating Hi-C and epigenetic data,\u00a0METALoci<\/i>\u00a0reconstructs 3D regulatory hubs, uncovering previously unknown interactions that\u00a0underlie\u00a0sex determination. Using this geostatistics-inspired method, researchers identified a regulatory region controlling\u00a0Fgf9<\/i>, a key gene that acts downstream of\u00a0Sry<\/i>\u00a0<\/i>\u00a0to trigger testis development, as well as\u00a0a previously unknown role for\u00a0Meis1\u00a0<\/i>and\u00a0Meis2<\/i>\u00a0genes\u00a0during sex differentiation. Together, these findings provide important insights and represent an important step towards understanding\u00a0Differences of Sex Development (DSD), a group of conditions that can affect reproductive capacity in humans.<\/p>\n
\u201cThe discovery of novel regulators of sex determination is particularly exciting, given that only a small number have been identified in recent decades,\u201d say Irene Mota-G\u00f3mez and Dar\u00edo Lupi\u00e1\u00f1ez, researchers at the CABD and first and corresponding authors of the study, respectively. \u201cIt also highlights how new genomic tools, such as\u00a0METALoci<\/i>, can uncover genes that traditional approaches may have overlooked.\u201d<\/p>\n
Beyond discovering this new rewiring regulatory mechanisms,\u00a0METALoci<\/i>\u00a0also provides a powerful approach to understand how the same gene can play distinct roles in different tissues. For example, deletion of the\u00a0Fgf9<\/i>\u00a0gonadal regulatory region in mice\u00a0 caused male-to-female sex reversal\u00a0but did not interfere with the role of the gene during lung development,\u00a0as it\u00a0rescued the perinatal lethality typically associated with\u00a0complete\u00a0Fgf9<\/i>\u00a0inactivation. This demonstrates how\u00a0METALoci<\/i>\u00a0can reveal how the same gene behaves differently across tissues, uncovering functions that would not be detected with conventional approaches.<\/p>\n