{"id":139774,"date":"2025-11-17T16:55:07","date_gmt":"2025-11-17T16:55:07","guid":{"rendered":"https:\/\/www.newsbeep.com\/nz\/139774\/"},"modified":"2025-11-17T16:55:07","modified_gmt":"2025-11-17T16:55:07","slug":"how-is-the-foxp3-gene-regulated","status":"publish","type":"post","link":"https:\/\/www.newsbeep.com\/nz\/139774\/","title":{"rendered":"How is the FOXP3 Gene Regulated?"},"content":{"rendered":"

Original story from the Gladstone Institutes (CA, USA).<\/a><\/p>\n

Fine-tuning a gene centrally involved in regulating the immune system offers potential clues for future autoimmunity and cancer treatments.<\/p>\n

The immune system faces a delicate balancing act: it must be aggressive enough to fight infections and cancer yet restrained enough to avoid attacking the body\u2019s own tissues.<\/p>\n

More than two decades ago, researchers identified a gene called\u00a0FOXP3\u00a0as playing a critical role in maintaining this balance and preventing autoimmune disease \u2013 work that garnered\u00a0this year\u2019s Nobel Prize in Physiology or Medicine.<\/a><\/p>\n

Now, scientists at Gladstone Institutes<\/a> (CA, USA) and UC San Francisco<\/a> (UCSF; CA, USA) have mapped the intricate network of genetic switches that immune cells use to fine-tune levels of\u00a0FOXP3. Their\u00a0findings have important implications for developing immune therapies and address a long-standing mystery about why this gene behaves differently in humans than in mice.<\/p>\n

\u201cFOXP3\u00a0is absolutely essential for regulating our immune systems,\u201d commented\u00a0Alex Marson<\/a>,\u00a0director of the Gladstone\u2013UCSF Institute of Genomic Immunology, who led the study. \u201cHow it\u2019s controlled is a fundamental question of immunology, and the detailed answer could offer clues to develop future therapies for autoimmune diseases or cancer.\u201d<\/p>\n

A search for dimmer switches<\/p>\n

The gene\u00a0FOXP3\u00a0is active in all regulatory T cells, which keep immune reactions in check. Without this gene, regulatory T cells cannot function properly and the immune system spirals out of control, attacking the body\u2019s own tissues. People with mutations in FOXP3 develop rare and severe autoimmune diseases.<\/p>\n

In mice,\u00a0FOXP3\u00a0is only switched on in regulatory T cells. But in humans, conventional T cells \u2013 the inflammatory cells that fight infections \u2013 can also briefly activate\u00a0FOXP3. This difference has puzzled immunologists for years.<\/p>\n

In the new work, Marson\u2019s lab used CRISPR-based gene silencing technology to systematically test 15,000 sites in the DNA surrounding the\u00a0FOXP3 gene. They were looking for genetic regulatory elements \u2013 nearby stretches of DNA that act like dimmer switches, controlling when and how much a gene is turned on or off.<\/p>\n

By disrupting thousands of locations in both human and mouse regulatory and conventional T cells and then measuring effects on\u00a0FOXP3\u00a0levels, the team identified which nearby DNA sequences control\u00a0FOXP3.<\/p>\n

\u201cWe essentially created a functional map of the entire\u00a0FOXP3\u00a0control system,\u201d explained Jenny Umhoefer, a former postdoctoral fellow in Marson\u2019s lab and first author of the paper.<\/p>\n

\"\"A synthetic regeneration cascade for genetically editing crops<\/a><\/p>\n

A research team has created gene-edited crops without using tissue culture.<\/p>\n

\u00a0<\/p>\n

Immune control panels<\/p>\n

The experiments revealed that different human cell types have different control systems for the gene\u00a0FOXP3. In regulatory T cells, where\u00a0FOXP3\u00a0must remain constantly active, multiple enhancers \u2013 DNA sequences that boost the levels of a gene \u2013 work together to ensure the gene stays on. Because they work redundantly, disrupting just one of those enhancers had only a small effect on\u00a0FOXP3\u00a0levels.<\/p>\n

In conventional T cells, only two enhancers were mapped. But the researchers also discovered an unexpected repressor that acts as a brake on the\u00a0FOXP3\u00a0gene.<\/p>\n

\u201cWhat we\u2019re seeing is a sophisticated regulatory circuit,\u201d Umhoefer shared. \u201cThe cell has gas pedals and brakes, and it coordinates them to achieve precise control.\u201d<\/p>\n

To understand not just where these genetic switches are located, but also what controls them, the team conducted a second massive CRISPR screen. This time, they systematically disrupted nearly 1350 genes throughout the genome to identify specific proteins that control\u00a0FOXP3\u00a0levels.<\/p>\n

Then, working with Gladstone Affiliate Investigator\u00a0Ansuman Satpathy<\/a>,\u00a0the team used a technique called ChIP-seq to physically map where the proteins are located on the DNA in relation to the\u00a0FOXP3\u00a0gene.<\/p>\n

\u201cThis was a big step forward in developing ways to link the local regulatory elements with the proteins that actually bind to them,\u201d commented Satpathy, who is also an associate professor in the Department of Pathology at the Stanford School of Medicine. \u201cNo one had put together these tools in such a broad, systematic way before.\u201d<\/p>\n

A species mystery<\/p>\n

Marson\u2019s lab had initially hypothesized that in humans, conventional T cells may have an enhancer to turn on\u00a0FOXP3\u00a0that is missing in mice, explaining why the mouse cells never flip the gene on. Surprisingly, they found that conventional T cells in mice have all the same enhancer elements as humans.<\/p>\n

The difference, the scientists realized, may lie in the repressor they discovered. In mouse conventional T cells, this repressor keeps\u00a0FOXP3\u00a0constantly off. When the researchers used CRISPR to delete the repressor from mice DNA, the conventional T cells began to express the\u00a0FOXP3\u00a0gene like human cells.<\/p>\n

\u201cThis was a striking result,\u201d Marson shared. \u201cBy removing a single repressive element, we could break the species difference and enable conventional T cells in mice to express\u00a0FOXP3. This offers new hints as to how regulation of key genes might evolve across species.\u201d<\/p>\n

The findings point to the importance of studying gene regulation in human cells and underscore the need to look broadly for repressors \u2013 not just the more common enhancer elements.<\/p>\n

Precision cell engineering<\/p>\n

The new study provides a foundation for ongoing efforts to discover and develop new treatments for a range of diseases. Armed with a full map of the different elements involved in controlling the levels of the\u00a0FOXP3\u00a0gene, researchers can begin to develop new ways of tweaking these levels for immunotherapies.<\/p>\n

Treatments for autoimmune diseases, for instance, may benefit from increased levels of\u00a0FOXP3, while treatments for cancer may work better with lower\u00a0FOXP3\u00a0activity.<\/p>\n

\u201cThere are enormous efforts right now to drug regulatory T cells, either to promote their activity or reduce it,\u201d Marson concluded. \u201cAs we understand new aspects of the circuitry that distinguishes regulatory T cells from conventional cells, we can think about strategies to rationally manipulate it.\u201d<\/p>\n

This article has been republished from the following\u00a0materials<\/a>.\u00a0Material may have been edited for length and\u00a0house style. For further information, please contact the cited source. Our press release publishing policy can be accessed\u00a0here<\/a>.<\/p>\n","protected":false},"excerpt":{"rendered":"Original story from the Gladstone Institutes (CA, USA). Fine-tuning a gene centrally involved in regulating the immune system…\n","protected":false},"author":2,"featured_media":139775,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[7],"tags":[95011,111,139,69,147,39481],"class_list":{"0":"post-139774","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-science","8":"tag-chip-seq","9":"tag-new-zealand","10":"tag-newzealand","11":"tag-nz","12":"tag-science","13":"tag-t-cell"},"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/posts\/139774","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/comments?post=139774"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/posts\/139774\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/media\/139775"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/media?parent=139774"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/categories?post=139774"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/tags?post=139774"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}