{"id":102983,"date":"2020-02-27T23:23:29","date_gmt":"2020-02-28T07:23:29","guid":{"rendered":"https:\/\/lifeboat.com\/blog\/2020\/02\/induction-of-anti-aging-gene-klotho-with-a-small-chemical-compound-that-demethylates-cpg-islands"},"modified":"2020-02-28T03:42:13","modified_gmt":"2020-02-28T11:42:13","slug":"induction-of-anti-aging-gene-klotho-with-a-small-chemical-compound-that-demethylates-cpg-islands","status":"publish","type":"post","link":"https:\/\/lifeboat.com\/blog\/2020\/02\/induction-of-anti-aging-gene-klotho-with-a-small-chemical-compound-that-demethylates-cpg-islands","title":{"rendered":"Induction of anti-aging gene klotho with a small chemical compound that demethylates CpG islands"},"content":{"rendered":"<p><a class=\"aligncenter blog-photo\" href=\"https:\/\/lifeboat.com\/blog.images\/induction-of-anti-aging-gene-klotho-with-a-small-chemical-compound-that-demethylates-cpg-islands4.jpg\"><\/a><\/p>\n<p>Klotho (KL) is described as an anti-aging gene because mutation of <em>Kl<\/em> gene leads to multiple pre-mature aging phenotypes and shortens lifespan in mice. Growing evidence suggests that an increase in KL expression may be beneficial for age-related diseases such as arteriosclerosis and diabetes. It remains largely unknown, however, how <em>Kl<\/em> expression could be induced. Here we discovered novel molecular mechanism for induction of <em>Kl<\/em> expression with a small molecule \u2018Compound H\u2019, <em>N<\/em>-(2-chlorophenyl)-1 <em>H<\/em>-indole-3-caboxamide. Compound H was originally identified through a high-throughput screening of small molecules for identifying <em>Kl<\/em> inducers. However, how Compound H induces <em>Kl<\/em> expression has never been investigated. We found that Compound H increased <em>Kl<\/em> expression <em>via<\/em> demethylation in CpG islands of the <em>Kl<\/em> gene. The demethylation was accomplished by activating demethylases rather than inhibiting methylases. Due to demethylation, Compound H enhanced binding of transcription factors, Pax4 and Kid3, to the promoter of the <em>Kl<\/em> gene. Pax4 and Kid3 regulated <em>Kl<\/em> promoter activity positively and negatively, respectively. Thus, our results show that demethylation is an important molecular mechanism that mediates Compound H-induced <em>Kl<\/em> expression. Further investigation is warranted to determine whether Compound H demethylates the <em>Kl<\/em> gene <em>in vivo<\/em> and whether it can serve as a therapeutic agent for repressing or delaying the onset of age-related diseases.<\/p>\n<p><strong class=\"\">Keywords: <\/strong>klotho, methylation, Pax4, Kid3, CpG island.<\/p>\n<p>Pre-mature aging phenotypes were eminent in the klotho (Kl)-deficient mice, which have ~ 10 copies of a transgene integrated in the 5\u2019 flanking region of the Kl gene disrupting its expression [1]. The klotho mice die around ~ 2 months of age after birth due to multiple aging-related organ failures [1]. Later, the role of KL in aging was confirmed by the reproduction of the same aging phenotypes in Kl knockout homozygous (Kl \u2212\/\u2212) mice [2]. On the other hand, overexpression of KL extends lifespan by 20\u201330% [2, 3]. The protein products of Kl gene can be divided into two forms: membrane-integrated form of Kl and non-integrated form of Kl which includes secreted and soluble Kl (sKl). These two type of proteins are produced from the two transcripts that arise from a single kl gene due to alternative RNA splicing [4, 5].<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Klotho (KL) is described as an anti-aging gene because mutation of Kl gene leads to multiple pre-mature aging phenotypes and shortens lifespan in mice. Growing evidence suggests that an increase in KL expression may be beneficial for age-related diseases such as arteriosclerosis and diabetes. It remains largely unknown, however, how Kl expression could be induced. [\u2026]<\/p>\n","protected":false},"author":513,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[11,412,269],"tags":[],"class_list":["post-102983","post","type-post","status-publish","format-standard","hentry","category-biotech-medical","category-genetics","category-life-extension"],"_links":{"self":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/102983","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/users\/513"}],"replies":[{"embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/comments?post=102983"}],"version-history":[{"count":1,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/102983\/revisions"}],"predecessor-version":[{"id":102990,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/102983\/revisions\/102990"}],"wp:attachment":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/media?parent=102983"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/categories?post=102983"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/tags?post=102983"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}