For decades, scientists viewed the genome of a newly fertilised egg as a structural ‘blank slate’ \u2013 a disordered tangle of DNA waiting for the embryo to ‘wake up’ and start reading its own genetic instructions.\u00a0<\/p>\n
In research published today in\u00a0Nature Genetics,\u00a0Professor Juanma\u00a0Vaquerizas\u00a0and his team\u00a0have\u00a0found\u00a0that a surprising level of structure is already in place.\u00a0They’ve\u00a0developed a\u00a0breakthrough technology, called\u00a0Pico-C, which enables scientists to see the\u00a03D\u00a0structure of the genome in unprecedented detail.\u00a0Using this technique, they\u00a0discovered that well before the genome fully awakens \u2013 a critical event known as Zygotic Genome Activation \u2013 a sophisticated 3D\u00a0scaffold\u00a0of DNA\u00a0is already being built.\u00a0Understanding how DNA folds in space matters because this\u00a0controls which genes can\u00a0be\u00a0turned\u00a0on\u00a0during development, helping cells function properly and preventing\u00a0developmental defects and\u00a0disease.\u00a0<\/p>\n
\nWe used to think of the time before the genome awakens as a period of chaos. But by zooming in closer than ever before, we can see that\u00a0it’s\u00a0actually a\u00a0highly disciplined construction site. The scaffolding of the genome is being erected in a precise, modular way, long before the ‘on’ switch is fully flipped.”\u00a0<\/p>\n
\u00a0Noura\u00a0Maziak, lead author of the study<\/p>\n<\/blockquote>\n
Pico-C: Seeing more with less\u00a0<\/p>\n
The\u00a0team’s discovery was made in\u00a0the fruit fly (Drosophila). In the first few hours after fertilisation, a fly embryo undergoes a rapid series of nuclear divisions, creating thousands of cells.\u00a0It’s\u00a0this high-speed environment that makes the fruit fly perfect for studying the fundamentals of genetics.\u00a0<\/p>\n
Using\u00a0their\u00a0ultra-sensitive\u00a0Pico-C\u00a0technology, they mapped the 3D\u00a0structure\u00a0of the\u00a0fruit fly\u00a0genome\u00a0during these early developmental stages.\u00a0They found that the 3D loops and folds of DNA follow a modular logic, allowing different inputs to regulate specific parts of the genome. It is a complex architectural programme that ensures the information encoded in the genome is ready for action the moment it is needed.\u00a0<\/p>\n
As well as providing high-resolution detail about\u00a0the shape of DNA,\u00a0Pico-C only\u00a0requires\u00a0tiny amounts of\u00a0sample\u00a0\u2013 ten times less than standard methods.\u00a0This opens the door to\u00a0opportunities\u00a0for\u00a0studying how DNA folding shapes gene regulation\u00a0and its implication in many diseases\u00a0in greater detail\u00a0than previously possible.\u00a0<\/p>\n
From fly embryos to human health\u00a0<\/p>\n
\u00a0While the ‘blueprint’ of this architecture was discovered in fruit flies, the importance of\u00a0maintaining\u00a0it applies directly to humans. In a companion study\u00a0published today in\u00a0Nature Cell Biology\u00a0led by\u00a0Professor Ulrike Kutay and\u00a0collaborators at\u00a0ETH Z\u00fcrich\u00a0in\u00a0Switzerland, the team\u00a0applied\u00a0this high-resolution mapping to human cells.\u00a0<\/p>\n
They investigated what happens when the ‘anchors’ that hold this 3D structure in place\u00a0are removed. The results were\u00a0striking:\u00a0when the architecture collapses, the human cell mistakes the structural failure for a viral attack. This triggers the\u00a0cell’s innate immune system, sounding a false alarm that can lead to inflammation<\/a> and disease.\u00a0<\/p>\n
“These two studies tell a complete story,” says\u00a0Juanma. “The first shows us how the genome’s 3D structure is carefully built at the start of life. The second shows us the disastrous consequences for human health if that structure is allowed to collapse.”\u00a0<\/p>\n
This study was funded by\u00a0the Medical Research Council and the Academy of Medical Sciences\u00a0(AMS)\u00a0through an AMS\u00a0Professorship\u00a0award.\u00a0<\/p>\n
Source:<\/p>\n
Medical Research Council (MRC) Laboratory of Medical Sciences<\/a><\/p>\n
Journal reference:<\/p>\n