A dual enhancer-attenuator element ensures transient Cdx2 expression during posterior body formation<\/a>\u201d uncovers how the duration of expression of the gene Cdx2 is tightly regulated by a newly identified DNA sequence element called an \u201cattenuator.\u201d<\/p>\n\u201cWe have been particularly interested in Cdx2 for many years now, because of its critical role in embryonic development, including the formation of the spinal cord,\u201d Metzis told GEN. \u201cAs Cdx2 plays such an important role, we wanted to understand what determines where and when a cell will express this critical factor.\u201d<\/p>\n
Cdx2 is expressed for a brief time during early development. The timing and duration of expression are pivotal to proper embryonic development. \u201cCdx2 is a key gene involved in shaping posterior body development, but its expression is extinguished really quickly,\u201d first author Ir\u00e8ne Amblard, PhD, told GEN. How the body controls this pulse of activity has remained unclear.<\/p>\n
Using CRISPR-Cas9 gene editing, the team systematically dissected the regulatory landscape around the Cdx2 gene. They identified multiple cis-regulatory elements (CREs) that enhance Cdx2 expression in vitro. They further identified a DNA element within the Cdx2 locus that does not fit the classical definitions of either an enhancer or a silencer. Instead, this element modifies, or attenuates, expression with temporal and tissue specificity.<\/p>\n
This attenuator modulates gene expression in a time- and cell-type-specific manner, unlike enhancers or silencers, which broadly switch genes on or off. Removing or mutating the attenuator significantly altered Cdx2 activity and disrupted normal body patterning in mouse embryos, leading to visibly malformed developmental structures.<\/p>\n
The researchers found that they could reprogram this attenuator to act as an enhancer by modifying just a single motif within its sequence. \u201cWhen we remove this region, we interfere with Cdx2 expression, and this impacts embryonic development,\u201d Metzis explained to GEN. \u201cWhat we also show is that by modifying the DNA sequence contained within the attenuator, we can reprogram the function of the element and its effect on Cdx2.\u201d<\/p>\n
To Amblard, one of the most striking moments came when comparing embryos with the attenuator knocked out. \u201cLooking at the embryo generated using CRISPR-Cas9 knockout technology targeted against the attenuator and observing that the shape is different compared to wildtype embryos was a very striking result,\u201d she shared with GEN. \u201cIt tells us that introducing subtle changes to the DNA can interfere with how an embryo develops.\u201d<\/p>\n
This dual behavior\u2014able to enhance or attenuate gene expression depending on context\u2014points to further complexity in the non-coding genome. \u201cOur findings establish a dual cis-regulatory logic ensuring precise spatiotemporal control over gene expression for vertebrate body patterning,\u201d the authors wrote.<\/p>\n
The implications reach beyond developmental biology. By revealing how gene expression can be precisely tuned\u2014not simply switched on or off\u2014this work opens new possibilities for synthetic biology and gene therapy. Programmable control of gene activity could offer a new approach for treating diseases caused by gene misregulation, from developmental disorders to cancer.<\/p>\n
\u201cWe\u2019re excited because previous research suggests that our genome may harbor many different types of elements that finely tune gene expression, but they\u2019ve not been easy to identify,\u201d said Metzis. \u201cIf we can address this challenge, this holds enormous potential for unlocking new ways to treat diseases by fine-tuning gene expression where and when it\u2019s needed.\u201d<\/p>\n
While more work is needed to explore the mechanisms through which this attenuator functions, Amblard said the next steps will focus on understanding how the element operates at a molecular level and what other genes may be similarly regulated.<\/p>\n
As researchers move toward precision control of gene expression, discoveries like this provide key stepping stones. Not only do they deepen our understanding of how the genome builds a body, they also hint at how we might one day rewrite its instructions for therapeutic benefit.<\/p>\n","protected":false},"excerpt":{"rendered":"A developing mouse embryo expresses different genes (green, magenta, cyan) from head to tail, to generate different parts…\n","protected":false},"author":2,"featured_media":219669,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3846],"tags":[86677,86678,86679,3898,267,46175,26716,70,21379,11920,23487,16,15],"class_list":{"0":"post-219668","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-genetics","8":"tag-crispr-cas9-technology","9":"tag-disease-modeling","10":"tag-gene-expression-regulation","11":"tag-genes","12":"tag-genetics","13":"tag-genome-editing","14":"tag-insights","15":"tag-science","16":"tag-therapeutics","17":"tag-topics","18":"tag-translational-medicine","19":"tag-uk","20":"tag-united-kingdom"},"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@uk\/114757569541408989","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts\/219668","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/comments?post=219668"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts\/219668\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/media\/219669"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/media?parent=219668"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/categories?post=219668"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/tags?post=219668"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
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