Anyone who\u2019s tried a weekend home improvement project knows that to do a job right, you\u2019ve got to have the right tools. For cells, these \u201ctools\u201d are proteins encoded by genes. The right genes for the job are turned on only in the specific cells where they are needed. And every cell in your body has a specific job to do. Cells in your pancreas have to produce insulin, while cells in the retina of your eye must be able to sense light and color. Like using the wrong tool for the job, if the wrong genes are turned on in a cell, it can cause a real mess. Worse, in some cases it can cause serious disease like cancer.<\/p>\n
Scientists have known this for decades. They\u2019ve also known that there are specific proteins called \u201ctranscription factors\u201d that control which genes are turned on or off in cells by binding to nearby DNA. Transcription factors were thought to act like a switch; they are either \u201con\u201d (bound to DNA) or \u201coff\u201d (not bound).<\/p>\n
A UNC-led team of scientists has now shown that transcription factors don\u2019t act like an \u2018on-off\u2019 switch, but instead can exhibit much more complex binding behavior.<\/p>\n
\u201cThis is a new way of looking at how genes are controlled,\u201d says Jason Lieb, study senior author.\u00a0 \u201cFor a while now there have been molecular maps that show the location of where the proteins are bound to DNA \u2013 like a roadmap.\u00a0 For the first time, we are able to show the molecular equivalent of a real-time traffic report.\u201d Their study appears in the April 12, 2012 issue of the journal Nature.<\/em> Lieb is a professor of biology in UNC\u2019s College of Arts and Sciences and a member of UNC Lineberger Comprehensive Cancer Center.<\/p>\n Working in yeast, the UNC team learned that the transcription factors\u2019 binding process is dynamic and involves more than just being bound or unbound. In addition to a stable binding state (on or off), the team demonstrates a state that they call \u201ctreadmilling,\u201d where no forward transcription process is occurring.\u00a0 Within this process, they hypothesize the existence of a molecular \u201cclutch\u201d that converts treadmilling to a stable bound state, moving the transcription process forward to completion to turn the gene on.<\/p>\n Lieb explains, \u201cThis discovery is exciting because we developed a new way to measure and calculate how long a protein is associated with all of the different genes it regulates. This is important because it represents a new step in the process of how genes are regulated. And with every new step, there are opportunities for new mechanisms of regulation.\u201d Lieb is director of the Carolina Center for Genome Sciences.<\/p>\n He adds, \u201cWe found that proteins that bind in the stable state are associated with high levels of gene transcription. We think that if we can regulate the transition between treadmilling and stable binding, we can regulate the outcome in terms of gene expression. Ultimately, this type of regulation could be important for genetic medicine \u2013 a new way to regulate the \u2018switches\u2019 that turn gene expression associated with disease on or off.\u201d<\/p>\n The team set up a controlled competition between two copies of the same transcription factor, each with a unique molecular tag. They let one of the proteins bind to all of its gene targets, then introduced the second copy. Next the team measured how long it took the competitor transcription factor to replace the resident protein and used this data to calculate the residence time at each location in the genome.\u00a0 Colin Lickwar, first author of the paper, says, \u201cWe didn\u2019t know if the residence time was important, but we found that the residence time was a much better indicator of whether a gene was turned on or off than previous measures of binding.\u201d<\/p>\n Anthony Carter, who oversees gene regulation grants at the National Institutes of Health\u2019s National Institute of General Medical Sciences, explains, \u201cBy taking an interdisciplinary approach that incorporates the use of mathematical modeling tools, Dr. Lieb has shed new light on a fundamental cellular process, the ability to quickly shift between active and inactive states of gene expression. The findings may offer new insights on how cells respond to developmental cues and how they adapt to changing\u00a0environmental conditions.\u201d The National Institute of General Medical Sciences partially supported the work.<\/p>\n Other UNC authors are: Sean E. Hanlon. Additional authors are James G. McNally and Florian Mueller, both from the Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health.<\/p>\n <\/p>\n <\/p>\n","protected":false},"excerpt":{"rendered":" UNC researchers have found that gene switches do more than just flip “on” or “off.” The specific proteins called transcription factors that control which genes are turned off or on actually exhibit much more complex binding behavior. For the first time, “we are able to show the molecular equivalent of a real-time traffic report,” says biologist Jason Lieb.<\/p>\n","protected":false},"author":4,"featured_media":2953,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"default","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","ast-disable-related-posts":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"footnotes":""},"categories":[17],"tags":[],"class_list":["post-2952","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-natural-sciences-mathematics"],"_links":{"self":[{"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=\/wp\/v2\/posts\/2952","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=\/wp\/v2\/users\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=2952"}],"version-history":[{"count":1,"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=\/wp\/v2\/posts\/2952\/revisions"}],"predecessor-version":[{"id":45229,"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=\/wp\/v2\/posts\/2952\/revisions\/45229"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=\/wp\/v2\/media\/2953"}],"wp:attachment":[{"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=2952"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=2952"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=2952"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}