{"129881":{"#nid":"129881","#data":{"type":"news","title":"Successful Stem Cell Differentiation Requires DNA Compaction, Study Finds","body":[{"value":"\u003Cp\u003ENew research findings show that embryonic stem cells unable to fully compact the DNA inside them cannot complete their primary task: differentiation into specific cell types that give rise to the various types of tissues and structures in the body.\u003C\/p\u003E\u003Cp\u003EResearchers from the Georgia Institute of Technology and Emory University found that chromatin compaction is required for proper embryonic stem cell differentiation to occur. Chromatin, which is composed of histone proteins and DNA, packages DNA into a smaller volume so that it fits inside a cell.\u0026nbsp;\u003C\/p\u003E\u003Cp\u003EA study published on May 10, 2012 in the journal \u003Cem\u003E\u003Ca href=\u0022http:\/\/dx.doi.org\/10.1371\/journal.pgen.1002691\u0022\u003EPLoS Genetics\u003C\/a\u003E\u003C\/em\u003E found that embryonic stem cells lacking several histone H1 subtypes and exhibiting reduced chromatin compaction suffered from impaired differentiation under multiple scenarios and demonstrated inefficiency in silencing genes that must be suppressed to induce differentiation.\u003C\/p\u003E\u003Cp\u003E\u201cWhile researchers have observed that embryonic stem cells exhibit a relaxed, open chromatin structure and differentiated cells exhibit a compact chromatin structure, our study is the first to show that this compaction is not a mere consequence of the differentiation process but is instead a necessity for differentiation to proceed normally,\u201d said \u003Ca href=\u0022http:\/\/www.biology.gatech.edu\/people\/yuhong-fan\/?id=yuhong-fan\u0022\u003EYuhong Fan\u003C\/a\u003E, an assistant professor in the \u003Ca href=\u0022http:\/\/www.biology.gatech.edu\/\u0022\u003EGeorgia Tech School of Biology\u003C\/a\u003E.\u003C\/p\u003E\u003Cp\u003EFan and \u003Ca href=\u0022http:\/\/www.bme.gatech.edu\/facultystaff\/faculty_record.php?id=78\u0022\u003ETodd McDevitt\u003C\/a\u003E, an associate professor in the \u003Ca href=\u0022http:\/\/www.bme.gatech.edu\/\u0022\u003EWallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University\u003C\/a\u003E, led the study with assistance from Georgia Tech graduate students Yunzhe Zhang and Kaixiang Cao, research technician Marissa Cooke, and postdoctoral fellow Shiraj Panjwani.\u003C\/p\u003E\u003Cp\u003EThe work was supported by the National Institutes of Health\u2019s National Institute of General Medical Sciences (NIGMS), the National Science Foundation, a Georgia Cancer Coalition Distinguished Scholar Award, and a Johnson \u0026amp; Johnson\/Georgia Tech Healthcare Innovation Award.\u003C\/p\u003E\u003Cp\u003ETo investigate the impact of linker histones and chromatin folding on stem cell differentiation, the researchers used embryonic stem cells that lacked three subtypes of linker histone H1 -- H1c, H1d and H1e -- which is the structural protein that facilitates the folding of chromatin into a higher-order structure. They found that the expression levels of these H1 subtypes increased during embryonic stem cell differentiation, and embryonic stem cells lacking these H1s resisted spontaneous differentiation for a prolonged time, showed impairment during embryoid body differentiation and were unsuccessful in forming a high-quality network of neural cells.\u003C\/p\u003E\u003Cp\u003E\u201cThis study has uncovered a new, regulatory function for histone H1, a protein known mostly for its role as a structural component of chromosomes,\u201d said Anthony Carter, who oversees epigenetics grants at NIGMS.\u0026nbsp; \u201cBy showing that H1 plays a part in controlling genes that direct embryonic stem cell differentiation, the study expands our understanding of H1\u2019s function and offers valuable new insights into the cellular processes that induce stem cells to change into specific cell types.\u201d\u003C\/p\u003E\u003Cp\u003EDuring spontaneous differentiation, the majority of the H1 triple-knockout embryonic stem cells studied by the researchers retained a tightly packed colony structure typical of undifferentiated cells and expressed high levels of Oct4 for a prolonged time. Oct4 is a pluripotency gene that maintains an embryonic stem cell\u2019s ability to self-renew and must be suppressed to induce differentiation.\u003C\/p\u003E\u003Cp\u003E\u201cH1 depletion impaired the suppression of the Oct4 and Nanog pluripotency genes, suggesting a novel mechanistic link by which H1 and chromatin compaction may mediate pluripotent stem cell differentiation by contributing to the epigenetic silencing of pluripotency genes,\u201d explained Fan. \u201cWhile a significant reduction in H1 levels does not interfere with embryonic stem cell self-renewal, it appears to impair differentiation.\u201d\u003C\/p\u003E\u003Cp\u003EThe researchers also used a rotary suspension culture method developed by McDevitt to produce with high efficiency homogonous 3D clumps of embryonic stem cells called embryoid bodies. Embryoid bodies typically contain cell types from all three germ layers -- the ectoderm, mesoderm and endoderm -- that give rise to the various types of tissues and structures in the body. However, the majority of the H1 triple-knockout embryoid bodies formed in rotary suspension culture lacked differentiated structures and displayed gene expression signatures characteristic of undifferentiated stem cells.\u003C\/p\u003E\u003Cp\u003E\u201cH1 triple-knockout embryoid bodies displayed a reduced level of activation of many developmental genes and markers in rotary culture, suggesting that differentiation to all three germ layers was affected.\u201d noted McDevitt. \u0026nbsp;\u003C\/p\u003E\u003Cp\u003EThe embryoid bodies also lacked the epigentic changes at the pluripotency genes necessary for differentiation, according to Fan.\u003C\/p\u003E\u003Cp\u003E\u201cWhen we added one of the deleted H1 subtypes to the embryoid bodies, Oct4 was suppressed normally and embryoid body differentiation continued,\u201d explained Fan. \u201cThe epigenetic regulation of Oct4 expression by H1 was also evident in mouse embryos.\u201d\u003C\/p\u003E\u003Cp\u003EIn another experiment, the researchers provided an environment that would encourage embryonic stem cells to differentiate into neural cells. However, the H1 triple-knockout cells were defective in forming neuronal and glial cells and a neural network, which is essential for nervous system development. Only 10 percent of the H1 triple-knockout embryoid bodies formed neurites and they produced on average eight neurites each. In contrast, half of the normal embryoid bodies produced, on average, 18 neurites.\u003C\/p\u003E\u003Cp\u003EIn future work, the researchers plan to investigate whether controlling H1 histone levels can be used to influence the reprogramming of adult cells to obtain induced pluripotent stem cells, which are capable of differentiating into tissues in a way similar to embryonic stem cells.\u003C\/p\u003E\u003Cp\u003E\u003Cem\u003EResearch reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under award number GM085261 and the National Science Foundation under award number CBET-0939511. The content is solely the responsibility of the principal investigators and does not necessarily represent the official views of the NIH or NSF.\u003C\/em\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EResearch News \u0026amp; Publications Office\u003Cbr \/\u003E Georgia Institute of Technology\u003Cbr \/\u003E 75 Fifth Street, N.W., Suite 314\u003Cbr \/\u003E Atlanta, Georgia 30308 USA\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EMedia Relations Contacts:\u003C\/strong\u003E Abby Robinson (abby@innovate.gatech.edu; 404-385-3364) or John Toon (jtoon@gatech.edu; 404-894-6986)\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EWriter: \u003C\/strong\u003EAbby Robinson\u003C\/p\u003E","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"\u003Cp\u003ENew research findings show that embryonic stem cells unable to fully compact the DNA inside them cannot complete their primary task: differentiation into specific cell types that give rise to the various types of tissues and structures in the body.\u003C\/p\u003E","format":"limited_html"}],"field_summary_sentence":[{"value":"New research findings show that embryonic stem cells unable to fully compact the DNA inside them cannot differentiate into specific cell types."}],"uid":"27206","created_gmt":"2012-05-10 18:24:11","changed_gmt":"2016-10-08 03:12:13","author":"Abby Vogel Robinson","boilerplate_text":"","field_publication":"","field_article_url":"","dateline":{"date":"2012-05-10T00:00:00-04:00","iso_date":"2012-05-10T00:00:00-04:00","tz":"America\/New_York"},"extras":[],"hg_media":{"129851":{"id":"129851","type":"image","title":"Impaired embryoid body differentiation","body":null,"created":"1449178634","gmt_created":"2015-12-03 21:37:14","changed":"1475894754","gmt_changed":"2016-10-08 02:45:54","alt":"Impaired embryoid body differentiation","file":{"fid":"194630","name":"embryoid-body-impaired-differentiation_hires.jpg","image_path":"\/sites\/default\/files\/images\/embryoid-body-impaired-differentiation_hires_0.jpg","image_full_path":"http:\/\/hg.gatech.edu\/\/sites\/default\/files\/images\/embryoid-body-impaired-differentiation_hires_0.jpg","mime":"image\/jpeg","size":223571,"path_740":"http:\/\/hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/embryoid-body-impaired-differentiation_hires_0.jpg?itok=L2avy-yE"}},"129861":{"id":"129861","type":"image","title":"Stem cell neural differentiation impairment","body":null,"created":"1449178634","gmt_created":"2015-12-03 21:37:14","changed":"1475894754","gmt_changed":"2016-10-08 02:45:54","alt":"Stem cell neural differentiation impairment","file":{"fid":"194631","name":"neural-impairment_hires.jpg","image_path":"\/sites\/default\/files\/images\/neural-impairment_hires_0.jpg","image_full_path":"http:\/\/hg.gatech.edu\/\/sites\/default\/files\/images\/neural-impairment_hires_0.jpg","mime":"image\/jpeg","size":75404,"path_740":"http:\/\/hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/neural-impairment_hires_0.jpg?itok=hSvnT-kk"}},"129871":{"id":"129871","type":"image","title":"Embryonic stem cell neural impairment","body":null,"created":"1449178634","gmt_created":"2015-12-03 21:37:14","changed":"1475894754","gmt_changed":"2016-10-08 02:45:54","alt":"Embryonic stem cell neural impairment","file":{"fid":"194632","name":"neural-impairment2_hires.jpg","image_path":"\/sites\/default\/files\/images\/neural-impairment2_hires_0.jpg","image_full_path":"http:\/\/hg.gatech.edu\/\/sites\/default\/files\/images\/neural-impairment2_hires_0.jpg","mime":"image\/jpeg","size":65712,"path_740":"http:\/\/hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/neural-impairment2_hires_0.jpg?itok=E8_4rfRJ"}}},"media_ids":["129851","129861","129871"],"groups":[{"id":"1188","name":"Research Horizons"}],"categories":[{"id":"145","name":"Engineering"},{"id":"146","name":"Life Sciences and Biology"},{"id":"135","name":"Research"}],"keywords":[{"id":"33241","name":"Chromatin"},{"id":"594","name":"college of engineering"},{"id":"4896","name":"College of Sciences"},{"id":"11533","name":"Department of Biomedical Engineering"},{"id":"13436","name":"embryoid bodies"},{"id":"33211","name":"Embryonic Stem Cell"},{"id":"33281","name":"Epigenetics"},{"id":"33221","name":"Histone"},{"id":"33231","name":"histone H1"},{"id":"33261","name":"linker histone h1"},{"id":"33251","name":"neural differentiation"}],"core_research_areas":[],"news_room_topics":[],"event_categories":[],"invited_audience":[],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[{"value":"\u003Cp\u003EAbby Robinson\u003Cbr \/\u003E Research News and Publications\u003Cbr \/\u003E \u003Ca href=\u0022mailto:abby@innovate.gatech.edu\u0022\u003Eabby@innovate.gatech.edu\u003C\/a\u003E\u003Cbr \/\u003E 404-385-3364\u003C\/p\u003E","format":"limited_html"}],"email":[],"slides":[],"orientation":[],"userdata":""}}}