Researchers led by Dubravka Vu\u010di\u0107evi\u0107 at the Max Delbr\u00fcck Center have developed a new method to discover how DNA controls genes. Their technique, published in \u201cCell Genomics,\u201d can reveal the genetic \u201cswitches\u201d that regulate important genes more quickly than existing methods.<\/p>\n
Most of the human genome does not code for proteins. Instead, much of it consists of regulatory regions. Like switches that turn lights on and off, these regions of nucleotides \u2013called transcriptional enhancers \u2013 determine where and when a gene is active, and largely control how much of the corresponding protein a cell produces. Defects in the genetic code of such regulatory elements can cause developmental defects and disease. But compared to protein-coding regions, they are difficult to identify because they are often located far from the genes they regulate and lack a well-defined genetic code.\u00a0<\/p>\n
Scientists at the Max Delbr\u00fcck Center led by Dr. Dubravka Vu\u010di\u0107evi\u0107 in the Computational and Regulatory Genomics lab of Professor Uwe Ohler have created a powerful new tool to uncover these regions that control our genes. Called\u00a0TargEted SingLe-cell Activation screen<\/p>\n
(TESLA-seq), it combines CRISPR-based gene activation (CRISPRa) \u2013 a\u00a0gene regulation technique that\u00a0uses\u00a0an engineered form of the CRISPR-Cas9 system to enhance the expression of specific genes\u00a0\u00ad\u2013 and targeted single-cell RNA sequencing to identify regulatory regions more quickly and accurately than other methods. The study was published in \u201cCell Genomics.\u201d<\/p>\n
\u201cWith this method, we can actually test how thousands of candidate regulatory elements in the genome are capable of switching genes on \u2013 and find out exactly what genes they influence,\u201d says Vu\u010di\u0107evi\u0107, lead author of the study.<\/p>\n
Mapping regulatory elements<\/p>\n
To showcase the technique, the study focused on a gene called\u00a0PHOX2B, which is essential for nervous system development. Mutations in the gene have been linked to neuroblastoma, a cancer of nervous system tissue that primarily affects children.\u00a0<\/p>\n
Vu\u010di\u0107evi\u0107 and her colleagues concentrated on a large area around PHOX2B. They designed two to three guide RNAs (gRNAs) to bind to sections of the DNA, or chunks, each 100 base pairs long. These gRNAs guided the CRISPR system to target locations in the genome. With a total of 46,722 gRNAs, they were able to scan the entire genomic landscape around the PHOX2B gene for potential gene switches.<\/p>\n
They then transferred each gRNA into a single human\u00a0neuroblastoma cell. The CRISPRa system then activated any regulatory regions that might have been present in the \u201cchunk.\u201d They identified more than 600 regions \u2013 called CaREs (CRISPRa-responsive elements) \u2013 that altered cell growth when activated.<\/p>\n
The team then zoomed in on about 200 CaREs in more detail and used targeted single-cell RNA sequencing to read out both the\u00a0gRNA inside each cell and the\u00a0RNA expressed from nearby genes. This allowed them to\u00a0link each CaRE to any of the over 70 genes in the PHOX2B region, whose expression changed\u00a0in\u00a0that cell.\u00a0They also found direct connections between CaREs and important regulators of\u00a0SHISA3\u00a0and\u00a0APBB2, which are involved in cancer and Alzheimer\u2019s disease.\u00a0<\/p>\n
Surprisingly, many CaREs controlled genes far away, skipping over nearby genes entirely \u2013 something other methods often miss. \u201cTESLA-seq doesn\u2019t just capture what’s happening in one cell type, it can reveal potential connections between genes and regulatory regions across different biological systems,\u201d says Ohler.\u00a0<\/p>\n
This is significant because many diseases affect more than a single tissue type, adds Vu\u010di\u0107evi\u0107. \u201cThe technique can be used to study the vast, uncharted parts of our DNA that influence health and disease across multiple organ systems and can help us to design more precise and effective therapies.\u201d<\/p>\n
Reference:\u00a0Vu\u010di\u0107evi\u0107 D, Hsu CW, Lopez Zepeda LS, et al. Sensitive dissection of a genomic regulatory landscape using bulk and targeted single-cell activation. Cell Genomics. 2025:100984. doi:\u00a010.1016\/j.xgen.2025.100984<\/a><\/p>\n This article has been republished from the following materials<\/a>. Note: material may have been edited for length and content. For further information, please contact the cited source. Our press release publishing policy can be accessed here<\/a>.<\/p>\n","protected":false},"excerpt":{"rendered":"Researchers led by Dubravka Vu\u010di\u0107evi\u0107 at the Max Delbr\u00fcck Center have developed a new method to discover how…\n","protected":false},"author":2,"featured_media":130679,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[25],"tags":[916,90,56,54,55],"class_list":["post-130678","post","type-post","status-publish","format-standard","has-post-thumbnail","category-genetics","tag-genetics","tag-science","tag-uk","tag-united-kingdom","tag-unitedkingdom"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/posts\/130678","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/comments?post=130678"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/posts\/130678\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/media\/130679"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/media?parent=130678"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/categories?post=130678"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/tags?post=130678"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}