{"id":9863,"date":"2015-02-12T11:49:46","date_gmt":"2015-02-12T16:49:46","guid":{"rendered":"https:\/\/college.unc.edu\/?p=9863"},"modified":"2024-07-02T16:07:05","modified_gmt":"2024-07-02T16:07:05","slug":"a-first-of-its-kind-tool-to-study-the-histone-code","status":"publish","type":"post","link":"https:\/\/collegearchive.unc.edu\/?p=9863","title":{"rendered":"A first of its kind tool to study the histone code"},"content":{"rendered":"
\"Robert<\/a>
Robert Duronio<\/figcaption><\/figure>\n

UNC scientists have created a new research tool, based on the fruit fly, to help crack the histone code. This research tool can be used to better understand the function of histone proteins, which play critical roles in the regulation of gene expression in animals and plants.<\/p>\n

This work, published in the journal<\/a> Developmental Cell<\/i>, opens the door to experiments that are expected to uncover new biology important for a host of conditions, such as neurological diseases, diabetes, obesity, and especially cancer, which has become a hotbed of epigenetic research.<\/p>\n

\u201cPeople think cancer is a disease of uncontrolled proliferation, but that\u2019s just one aspect of it,\u201d said Robert Duronio, professor of biology and genetics and co-senior author. \u201cCancer is actually a disease of development in which the cells don\u2019t maintain their proper functions; they don\u2019t do what they\u2019re supposed to be doing.\u201d Somehow, the gene regulation responsible for proper cell development goes awry.<\/p>\n

One aspect of gene regulation involves enzymes placing chemical tags or modifications on histone proteins \u2013 which control a cell\u2019s access to the DNA sequences that make up a gene. Properly regulated access allows cells to develop, function, and proliferate normally. The chemical modification of histones is thought to be a form of epigenetic information \u2013 information separate from our DNA \u2013 that controls gene regulation. This idea is based on the study of the enzymes that chemically modify histones. However, there is a flaw in this argument.<\/p>\n

\"Daniel<\/a>
Daniel McKay<\/figcaption><\/figure>\n

\u201cIn complex organisms, such as fruit flies, mice, and humans, scientists have only been able to infer <\/i>how these enzymes mechanistically accomplish their tasks,\u201d said Daniel McKay, assistant professor of genetics and biology and first author of the paper. \u201cIt\u2019s been technically impossible to directly study the role of histone modifications. Now, through our collaboration between UNC biologists, we\u2019ve been able to develop a tool in fruit flies to directly test the function of histones independently of the enzymes that modify them.\u201d<\/p>\n

This is crucial because therapies, such as cancer drugs, can target histones. With this new research tool, scientists will be able to better study thousands of enzyme-histone interactions important for human health.<\/p>\n

\u201cIf you think of the genome as a recipe book, then you could say we\u2019ve made it possible to know that there are hidden ingredients that help explain how specific recipes turn out correctly or not,\u201d said Greg Matera, professor of biology and genetics and co-senior author of the paper.\u00a0 \u201cThat\u2019s the first step in scientific discovery \u2013 knowing that there are things we need to look for and then searching for them.\u201d<\/p>\n

Beyond Yeast<\/strong><\/p>\n

Before now, a lot of this epigenetic research had been done in yeast \u2013 single cell organisms that also use enzymes to lay chemical tags on histone proteins. This work has yielded many interesting findings and has led to the development of therapeutics. But some of this work has led to an oversimplification of human biology, leaving many questions about human health unanswered.<\/p>\n

For instance, in complex organisms, enzymes in cells typically do more than one thing. One likely reason for this is that animals undergo cellular differentiation; human life begins as a single cell that differentiates into the various cell types needed for different organs, body parts, blood, the immune system, etc. This differentiation has to be maintained throughout life.<\/p>\n

\"Gregory<\/a>
Gregory Matera<\/figcaption><\/figure>\n

\u201cBecause of this, animals likely have a greater requirement for epigenetic regulation than yeast do,\u201d Matera said. \u201cAnimal cells have to \u2018remember\u2019 that they must express genes in specific ways.\u201d When cancer cells start dividing rapidly to form tumors, these cells are actually reverting to an earlier time in their development when they were supposed to divide rapidly. The gene regulation that was supposed to rein them in has gone haywire.<\/p>\n

Whereas in yeast, a histone-modifying enzyme might have a single regulatory task, the human version of that same enzyme might have other regulatory tasks that involve additional proteins.<\/p>\n

\u201cIn fact, maybe the really critical target of that one modifying enzyme is some other protein that we don\u2019t know about yet,\u201d Matera said. \u201cAnd we need to know about it.\u201d<\/p>\n

The best way to figure that out would be to make it impossible for the enzyme to modify a histone by changing \u2013 or mutating \u2013 the histone protein. If a histone protein could be disabled in this way and cells still behaved normally, then that would mean there was some other protein that the enzyme acted on. To do this, however, would require replacing a histone gene with a genetically engineered one that could not be modified by an enzyme.<\/p>\n

The problem is that in animals, such as mice and humans, there are many histone genes and they are scattered throughout the genome. This makes replacing them with \u2018designer\u2019 histone genes difficult.\u00a0 In addition, other genes are located in between the histone genes. Therefore, deleting the portion of the chromosome with histone genes in order to replace them with a modified one would wind up deleting other genes vital for survival. This would make such an approach in, say, a mouse, useless.<\/p>\n

\u201cIt has been technically impossible to do this kind of research in complex organisms,\u201d Duronio said. \u201cBut fruit flies have all their histone genes in one place on the chromosome; this makes it feasible to delete the normal genes and replace them with designer genes.\u201d<\/p>\n

Designer genes<\/strong><\/p>\n

Matera, Duronio, and McKay led an effort to delete the histone genes in fruit flies and replace them with specific designer histone genes they created. These new genes were created so they could not be the repositories of epigenetic tags or modifications. That is, the modifying enzyme would not be able to do its job on that<\/i> particular protein.<\/p>\n

As shown in the Developmental Cell<\/i> paper, the researchers put their new tool to the test. They \u201cbroke\u201d one histone protein that had been identified to interact in a specific way with a modifying enzyme, and they got the outcome in fruit flies they expected. But for another enzyme-histone interaction, the researchers got an unexpected result.<\/p>\n

Previously, in mammalian cells, other researchers had discovered that when you mutate a specific modifying enzyme, the result is death because the cells can\u2019t replicate.<\/p>\n

With their new fruit fly research model, the UNC researchers altered the histone gene so that this particular enzyme could not modify its histone protein target. The result was not death. In fact, the flies lived and flew as normal flies do. This meant that the enzyme, which was previously proven to be vital to life, must do something else very important.<\/p>\n

\u201cThere must be another target for that modifying enzyme,\u201d Matera said. \u201cThere must be another hidden carrier of epigenetic information that we don\u2019t know about.\u201d<\/p>\n

McKay added, \u201cThis is a demonstration of the potential of our epigenetic platform. Going forward, we\u2019re going to do a lot more experiments to identify more discrepancies and hopefully other targets of these enzymes. We\u2019re on the ground floor of a long-term project.\u201d<\/p>\n

This research shows that the epigenetic recipe book for yeast is thin. The recipe book for humans, which is genetically akin to the one for fruit flies, is much thicker, more complex, and full of hidden ingredients scientists have yet to discover.<\/p>\n

Now, scientists have a tool to test the recipes.<\/p>\n

Brian Strahl, professor of biochemistry and Biophysics in the School of Medicine, is also a principal investigator of this study. Duronio, Matera, and McKay are professors in the UNC School of Medicine and the College of Arts and Sciences.<\/i><\/p>\n

Strahl, Duronio, and Matera are members of the UNC Lineberger Comprehensive Cancer center. <\/i>Matera, Duronio, and McKay are members of the Integrative Program for Biological and Genome Sciences. Duronio is the director of the program.<\/i><\/p>\n

Story by Mark Derewicz, UNC Health Care<\/a><\/em><\/p>\n","protected":false},"excerpt":{"rendered":"

UNC scientists have created a new research tool, based on the fruit fly, to help crack the histone code. This research tool can be used to better understand the function of histone proteins, which play critical roles in the regulation of gene expression in animals and plants.<\/p>\n","protected":false},"author":4,"featured_media":0,"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-9863","post","type-post","status-publish","format-standard","hentry","category-natural-sciences-mathematics"],"_links":{"self":[{"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=\/wp\/v2\/posts\/9863","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=9863"}],"version-history":[{"count":1,"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=\/wp\/v2\/posts\/9863\/revisions"}],"predecessor-version":[{"id":47172,"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=\/wp\/v2\/posts\/9863\/revisions\/47172"}],"wp:attachment":[{"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=9863"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=9863"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/collegearchive.unc.edu\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=9863"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}