{"id":13327,"date":"2017-05-04T00:00:02","date_gmt":"2017-05-04T07:00:02","guid":{"rendered":"https:\/\/vermont.salk.edu\/?post_type=disclosure&#038;p=13327"},"modified":"2024-01-30T15:10:45","modified_gmt":"2024-01-30T23:10:45","slug":"novel-tool-confers-targeted-stable-editing-epigenome-human-stem-cells","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/zh\/news-release\/novel-tool-confers-targeted-stable-editing-epigenome-human-stem-cells\/","title":{"rendered":"Novel tool confers targeted, stable editing of epigenome in human stem cells"},"content":{"rendered":"<p>LA JOLLA\u2014Salk Institute scientists have developed a novel technology to correct disease-causing aberrations in the chemical tags on DNA that affect how genes are expressed. These types of chemical modifications, collectively referred to as epigenetics or the epigenome, are increasingly being considered as important as the genomic sequence itself in development and disease.<\/p>\n<div class=\"row\" style=\"\"><div class=\"col-md-10 col-md-push-1\"><div class=\"video-anchor\" id=\"video-LZWColoHkmc\"><\/div><div class=\"embed-responsive embed-responsive-16by9\"> <iframe class=\"embed-responsive-item\" src=\"\/\/www.youtube.com\/embed\/LZWColoHkmc?rel=0\" webkitallowfullscreen mozallowfullscreen allowfullscreen><\/iframe><\/div><!-- .embed-responsive --><\/div><!-- .col-md-*size --><\/div><!-- .\/row -->\n<p>The new Salk technology, which is described in the journal <a href=\"http:\/\/science.sciencemag.org\/content\/356\/6337\/503\" target=\"_blank\" rel=\"noopener\"><em>\u79d1\u5b66<\/em><\/a> on May 4, 2017, was used to model mutations in the epigenome associated with colon cancer and to restore proper methylation patterns in stem cells derived from patients suffering from Angelman syndrome (AS), a rare neurodegenerative disorder often misdiagnosed as autism. In addition to modeling and treating epigenetic disorders, the technology also holds promise for studying human development and biology in general.<\/p>\n<p>\u201cWe are excited at how many new avenues this work opens up for understanding disease processes and developing effective new therapies,\u201d says Salk Professor <a href=\"https:\/\/www.salk.edu\/zh\/scientist\/juan-carlos-izpisua-belmonte\/\">Juan Carlos Izpisua Belmonte<\/a>, senior author of the paper and holder of Salk\u2019s Roger Guillemin Chair. \u201cIt was a giant step to discover how to edit the genome\u2014this technology to edit the epigenome is another leap forward.\u201d<\/p>\n<figure id=\"attachment_13331\"  class=\"wp-caption alignright\"><img loading=\"lazy\" decoding=\"async\" width=\"300\" height=\"300\" class=\"img-responsive wp-image-13331 size-pr-300\" src=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/corrected-AS-neuron-300x300.jpg\" alt=\"Neurons from Angelman syndrome (AS) patients lack expression of the UBE3A protein due to an epigenetic defect. The new Salk technology restores normal expression of the UBE3A protein in neurons derived from the cells of an AS patient by correcting the aberrant methylation pattern (pictured).\" srcset=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/corrected-AS-neuron-300x300.jpg 300w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/corrected-AS-neuron-150x150.jpg 150w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/corrected-AS-neuron-768x768.jpg 768w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/corrected-AS-neuron-767x767.jpg 767w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/corrected-AS-neuron-147x147.jpg 147w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/corrected-AS-neuron-458x458.jpg 458w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/corrected-AS-neuron-585x585.jpg 585w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/corrected-AS-neuron-553x553.jpg 553w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/corrected-AS-neuron-750x750.jpg 750w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/corrected-AS-neuron-945x945.jpg 945w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/corrected-AS-neuron.jpg 1024w\" sizes=\"auto, (max-width: 300px) 100vw, 300px\" \/><figcaption class=\"wp-caption-text\">Neurons from Angelman syndrome (AS) patients lack expression of the UBE3A protein due to an epigenetic defect. The new Salk technology restores normal expression of the UBE3A protein in neurons derived from the cells of an AS patient by correcting the aberrant methylation pattern (pictured). <\/p>\n<p> <a href=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/corrected-AS-neuron.jpg\" target=\"_blank\" rel=\"noopener\">Click here<\/a> for a high-resolution image. Credit: Salk Institute\/Waitt Center<\/figcaption><\/figure>\n<p>Izpisua Belmonte\u2019s lab <a href=\"https:\/\/www.salk.edu\/zh\/news-release\/new-gene-editing-technology-partially-restores-vision-blind-animals\/\">recently pioneered a method<\/a> to modify genes in non-dividing cells, which make up the majority of adult tissues. The new technique goes beyond genes to target the most common type of epigenetic change, called DNA methylation, in which chemical tags called methyl groups attach to DNA. Typically these tags mark the gene as ready to be turned on or off. More and more, scientists are learning that DNA methylation is involved in a range of physiological and pathological processes from embryonic development to the onset of certain diseases later in life, including cancer. Researchers have discovered ways of altering methylation status on short DNA sequences, but no one has been able to make the changes stick over a broad range (a prerequisite for proper gene activation or inactivation) until now.<\/p>\n<p>Because 80 percent of mammalian DNA is methylated, the Izpisua Belmonte lab was curious about regions that are unmethylated. Paradoxically, these regions are often rich in potential methylation sites and tend to be close to regions of genes where transcription of genetic information begins. Yet somehow these regions, which are called CpG islands, normally remain unmethylated.<\/p>\n<figure id=\"attachment_13340\"  class=\"wp-caption alignleft\"><img loading=\"lazy\" decoding=\"async\" width=\"300\" height=\"207\" class=\"img-responsive wp-image-13340 size-pr-300\" src=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/2017-04-26_14-32-19-300x207.jpg\" alt=\"\" srcset=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/2017-04-26_14-32-19-300x207.jpg 300w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/2017-04-26_14-32-19-768x529.jpg 768w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/2017-04-26_14-32-19-1024x706.jpg 1024w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/2017-04-26_14-32-19-147x101.jpg 147w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/2017-04-26_14-32-19-458x316.jpg 458w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/2017-04-26_14-32-19-585x403.jpg 585w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/2017-04-26_14-32-19-553x381.jpg 553w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/2017-04-26_14-32-19-750x517.jpg 750w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/2017-04-26_14-32-19-945x651.jpg 945w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/2017-04-26_14-32-19.jpg 1515w\" sizes=\"auto, (max-width: 300px) 100vw, 300px\" \/><figcaption class=\"wp-caption-text\">This illustration represents editing of the epigenome by the new Salk technology. Top: open circles indicate aberrant methylation of the disease state. Bottom: Black circles indicate proper methylation induced by precise insertion of CpG-free DNA into a CpG island. The Salk team tested the technology in modeling colon cancer epimutations in human pluripotent cells, and to correct epigenetic defects in cells from a patient with Angelman syndrome (AS). <\/p>\n<p> <a href=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/2017-04-26_14-32-19.jpg\" target=\"_blank\" rel=\"noopener\">Click here<\/a> for a high-resolution image <\/p>\n<p> Credit: Salk Institute<\/figcaption><\/figure>\n<p>The researchers hypothesized that interfering with CpG islands might trigger new methylation. To test this hypothesis, the team first used molecular tools to insert DNA without CpGs into the island close to the <em>MLH1<\/em> gene. <em>MLH1<\/em> is normally unmethylated but leads to an increased risk of colon cancer if it becomes methylated. The team was able to mimic the aberrant methylation in the colon cancer gene as a proof of principle to begin to understand how abnormal methylation is associated with cancers.<\/p>\n<p>\u201cWhat is interesting about CpG islands is that they resist methylation,\u201d says Yuta Takahashi, a Salk research associate and first author of the paper. \u201cBut by introducing CpG-free DNA, we can override the machinery that blocks it and then induce DNA methylation of the entire island.\u201d<\/p>\n<p>Knowing they could induce methylation where it doesn\u2019t belong, the team next tried to attach methyl tags where they do belong on a genome but are missing, such as in some diseases. Angelman syndrome (AS) results from aberrant DNA methylation, which causes a loss of the UBE3A protein in neurons. This leads to cognitive deficits in patients. By using their technology, the team corrected the abnormal DNA methylation and restored UBE3A protein levels in AS neuronal cells in a dish.<\/p>\n<figure id=\"attachment_13330\"  class=\"wp-caption alignright\"><img loading=\"lazy\" decoding=\"async\" width=\"300\" height=\"200\" class=\"img-responsive wp-image-13330 size-pr-300\" src=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/belmonte0X8C9936methylation-300x200.jpg\" alt=\"From left (back): Concepcion Rodriguez Esteban, Jun Wu, Keiichiro Suzuki, Paloma Martinez Redondo (front): Maxim Shokhirev, Yuta Takahashi, Juan Carlos Izpisua Belmonte, Reyna Hernandez-Benitez\" srcset=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/belmonte0X8C9936methylation-300x200.jpg 300w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/belmonte0X8C9936methylation-768x512.jpg 768w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/belmonte0X8C9936methylation-1024x683.jpg 1024w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/belmonte0X8C9936methylation-147x98.jpg 147w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/belmonte0X8C9936methylation-458x305.jpg 458w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/belmonte0X8C9936methylation-585x390.jpg 585w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/belmonte0X8C9936methylation-553x369.jpg 553w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/belmonte0X8C9936methylation-750x500.jpg 750w, https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/belmonte0X8C9936methylation-945x630.jpg 945w\" sizes=\"auto, (max-width: 300px) 100vw, 300px\" \/><figcaption class=\"wp-caption-text\">From left (back): Concepcion Rodriguez Esteban, Jun Wu, Keiichiro Suzuki, Paloma Martinez Redondo (front): Maxim Shokhirev, Yuta Takahashi, Juan Carlos Izpisua Belmonte, Reyna Hernandez-Benitez <\/p>\n<p> <a href=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/belmonte0X8C9936methylation.jpg\" target=\"_blank\" rel=\"noopener\">Click here<\/a> for a high-resolution image. Credit: Salk Institute<\/figcaption><\/figure>\n<p>Most exciting, according to the researchers, was the fact that all the methylation patterns they introduced were stable over time, which has not been true of other epigenetic technologies. Even removing the CpG-free DNA did not affect the new methylation. The finding offers a way to rewrite epigenetic marks on CpG islands, as well as providing insight into the mechanism by which CpG islands are protected from DNA methylation.<\/p>\n<p>\u201cIt\u2019s wonderful that we have developed a new technology that allows for robust editing of the DNA methylome at CpG islands in pluripotent stem cells, which will help develop cell-replacement therapeutics for epigenetic disorders,\u201d says Jun Wu, a Salk staff scientist and one of the paper\u2019s coauthors. \u201cBut by discovering the underlying mechanisms of DNA methylation, we hope to do even more with this technology.\u201d<\/p>\n<p>Other authors included Keiichiro Suzuki, Paloma Martinez Redondo, Mo Li, Hsin-Kai Liao, Min-Zu Wu, Reyna Hern\u00e1ndez-Ben\u00edtez, Tomoaki Hishida, Maxim Nikolaievich Shokhirev, Concepcion Rodriguez Esteban and Ignacio Sancho-Martinez of the Salk Institute.<\/p>\n<p>The work was funded by the <a href=\"https:\/\/www.nih.gov\/about-nih\/what-we-do\/nih-almanac\/national-cancer-institute-nci\" target=\"_blank\" rel=\"noopener\">NIH\u2013National Cancer Institute (NCI)<\/a>, the <a href=\"http:\/\/www.chapmantrusts.org\/\" target=\"_blank\" rel=\"noopener\">Chapman Foundation<\/a>, and The <a href=\"http:\/\/helmsleytrust.org\/\" target=\"_blank\" rel=\"noopener\">Leona M. and Harry B. Helmsley Charitable Trust<\/a>, <a href=\"http:\/\/international.ucam.edu\/\" target=\"_blank\" rel=\"noopener\">UCAM<\/a> and the <a href=\"http:\/\/www.mathersfoundation.org\/\" target=\"_blank\" rel=\"noopener\">G. Harold and Leila Y. Mathers Charitable Foundation<\/a>.<\/p>","protected":false},"featured_media":13329,"template":"","faculty":[85],"disease-research":[333,146],"class_list":["post-13327","disclosure","type-disclosure","status-publish","has-post-thumbnail","hentry","faculty-juan-carlos-izpisua-belmonte","disease-research-genetics","disease-research-aging-and-regenerative-medicine"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.3 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Novel tool confers targeted, stable editing of epigenome in human stem cells - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/zh\/news-release\/novel-tool-confers-targeted-stable-editing-epigenome-human-stem-cells\/\" \/>\n<meta property=\"og:locale\" content=\"zh_CN\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Novel tool confers targeted, stable editing of epigenome in human stem cells - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"LA JOLLA\u2014Salk Institute scientists have developed a novel technology to correct disease-causing aberrations in the chemical tags on DNA that affect how genes are expressed. These types of chemical modifications, collectively referred to as epigenetics or the epigenome, are increasingly being considered as important as the genomic sequence itself in development and disease.\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.salk.edu\/zh\/news-release\/novel-tool-confers-targeted-stable-editing-epigenome-human-stem-cells\/\" \/>\n<meta property=\"og:site_name\" content=\"Salk Institute for Biological Studies\" \/>\n<meta property=\"article:modified_time\" content=\"2024-01-30T23:10:45+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2017\/05\/corrected-AS-neuron-767.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"767\" \/>\n\t<meta property=\"og:image:height\" content=\"767\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data1\" content=\"6 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/novel-tool-confers-targeted-stable-editing-epigenome-human-stem-cells\\\/\",\"url\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/novel-tool-confers-targeted-stable-editing-epigenome-human-stem-cells\\\/\",\"name\":\"Novel tool confers targeted, stable editing of epigenome in human stem cells - 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