ROVIDENCE, R.I. [Brown University] \u00e2\u20ac\u201d Cellular senescence \u00e2\u20ac\u201d when a cell can no longer divide \u00e2\u20ac\u201d is a programmed stage in a cell\u00e2\u20ac\u2122s life cycle. Sometimes, as in aging, we wish it didn\u00e2\u20ac\u2122t happen so much and sometimes, as in cancer, we wish it would happen more. Given its important impacts on health, biologists wish they could explain more about what\u00e2\u20ac\u2122s happening in cells when senescence takes hold. A new study helps by showing that chromosomes become somewhat transformed, altering their patterns of gene expression.<\/p>\n
\u00e2\u20ac\u0153There is a reconfiguration of their three-dimensional structure, which was kind of unexpected in my opinion,\u00e2\u20ac\u009d said Nicola Neretti, assistant professor of biology at Brown University and senior author of the study in Science Advances<\/em>.<\/p>\n Overall, Neretti\u00e2\u20ac\u2122s team found, chromosomes become much more compact, though some parts of them expand in volume. An analysis of their spatial organization finds that most genes move into areas called \u00e2\u20ac\u0153B\u00e2\u20ac\u009d compartments that are locked down by tightly wound chromatin that prevents their expression. Many, however, move into \u00e2\u20ac\u0153A\u00e2\u20ac\u009d compartments that are looser and therefore more open for gene expression.<\/p>\n The kinds of genes affected by these changes are often ones of relevance to senescence. In their analysis, for example, the scientists found that about one in eight genes associated with cell proliferation and other relevant cell functions switch from relatively loose A compartments to more restrictive B compartments.<\/p>\n The study combined two techniques. \u00e2\u20ac\u0153Hi-C\u00e2\u20ac\u009d chromosome conformation capture, first published in 2009, allowed them to discover the changes in genes\u00e2\u20ac\u2122 positioning in A or B chromatin compartments. Meanwhile, with the imaging technique \u00e2\u20ac\u0153FISH\u00e2\u20ac\u009d (fluorescence in situ hybridization) they fluorescently labeled different points on the chromosome to directly measure the physical distance between them. That revealed overall physical changes such as the size and compactness of the chromosomes before and after senescence. Researchers further imaged chromosomes using many FISH probes, a technique called \u00e2\u20ac\u0153chromosome paint,\u00e2\u20ac\u009d allowing them to highlight whole individual chromosomes and their constituent parts within the nucleus.<\/p>\n \u00e2\u20ac\u0153The Hi-C gives you a lot of information about what\u00e2\u20ac\u2122s happening locally in the genome, but doesn\u00e2\u20ac\u2122t give you information about the physical distances, so that\u00e2\u20ac\u2122s why we moved to FISH,\u00e2\u20ac\u009d Neretti said. \u00e2\u20ac\u0153We \u00e2\u20ac\u02dcfished\u00e2\u20ac\u2122 out the distances.\u00e2\u20ac\u009d<\/p>\n FISH and chromosome paint, for example, showed which parts of the chromosome got more compact and which expanded. In their research, the scientists saw that while the chromosomes\u00e2\u20ac\u2122 arms and the \u00e2\u20ac\u0153telomeres\u00e2\u20ac\u009d at their tips scrunched up, the relatively tiny middle \u00e2\u20ac\u201d the centromere \u00e2\u20ac\u201d expanded. Within the centromere certain areas of repetitive DNA called alpha satellites expanded dramatically and become expressed.<\/p>\n All of this information allowed them to create the first 3-D models of how chromosomes change in senescent cells, Neretti said.<\/p>\n Graduate student Steven Criscione of Neretti\u00e2\u20ac\u2122s lab and postdoctoral fellow Marco De Cecco of John Sedivy\u00e2\u20ac\u2122s lab co-led the work. Neretti also praised the contributions of two undergraduate co-authors Benjamin Siranosian and Yue Zhang.<\/p>\n The results follow a study two years ago by many of the same authors, also including Jill Kreiling, assistant professor (research) of biology. They showed that a molecular corollary of aging is that senescent cells lose their tight chromatin grip on often-harmful sequences of DNA called transposons, leading to greater replication of those \u00e2\u20ac\u0153rogue\u00e2\u20ac\u009d elements.<\/p>\n Now the team is delving deeper into the compartment switches (between A and B) that change the regulation of genes in senescent vs. nonsenescent cells, Neretti said. They hope to understand and model those transitions and their consequences in greater detail.<\/p>\n The new research helps to answer a fundamental question about what genetic changes come along with senescence, Neretti said. That answer might eventually take on clinical significance. Now that they know something about the physical changes afoot in chromosomes, scientists could look for the proteins that likely mediate these changes, he said. Down the road, perhaps, targeting these proteins could provide a way to slow down senescence or to speed it up.<\/p>\n ###<\/p>\n The National Institutes of Health funded the study (grants K25 AG028753 K25AG028753-03S1, R37 AG016694, R56 AG050582-01, F31AG050365, and K01AG039410).<\/p>\n","protected":false},"excerpt":{"rendered":" ROVIDENCE, R.I. [Brown University] \u00e2\u20ac\u201d Cellular senescence \u00e2\u20ac\u201d when a cell can no longer divide \u00e2\u20ac\u201d is a programmed stage in a cell\u00e2\u20ac\u2122s life cycle. Sometimes, as in aging, we wish it didn\u00e2\u20ac\u2122t happen so much and sometimes, as in cancer, we wish it would happen more. Given its important impacts on health, biologists wish Read More<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[],"tags":[],"class_list":["post-67981","post","type-post","status-publish","format-standard","hentry"],"_links":{"self":[{"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/posts\/67981","targetHints":{"allow":["GET"]}}],"collection":[{"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/comments?post=67981"}],"version-history":[{"count":0,"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/posts\/67981\/revisions"}],"wp:attachment":[{"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/media?parent=67981"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/categories?post=67981"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/tags?post=67981"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}