title: Histone chaperone APLF regulates induction of pluripotency in murine fibroblasts.
abstract: Induction of pluripotency in differentiated cells through the exogenous expression of the transcription factors Oct4, Sox2, Klf4 and cellular Myc involves reprogramming at the epigenetic level. Histones and their metabolism governed by histone chaperones constitute an important regulator of epigenetic control. We hypothesized that histone chaperones facilitate or inhibit the course of reprogramming. For the first time, we report here that the downregulation of histone chaperone Aprataxin PNK-like factor (APLF) promotes reprogramming by augmenting the expression of E-cadherin (Cdh1), which is implicated in the mesenchymal-to-epithelial transition (MET) involved in the generation of induced pluripotent stem cells (iPSCs) from mouse embryonic fibroblasts (MEFs). Downregulation of APLF in MEFs expedites the loss of the repressive MacroH2A.1 (encoded by H2afy) histone variant from the Cdh1 promoter and enhances the incorporation of active histone H3me2K4 marks at the promoters of the pluripotency genes Nanog and Klf4, thereby accelerating the process of cellular reprogramming and increasing the efficiency of iPSC generation. We demonstrate a new histone chaperone (APLF)-MET-histone modification cohort that functions in the induction of pluripotency in fibroblasts. This regulatory axis might provide new mechanistic insights into perspectives of epigenetic regulation involved in cancer metastasis.
authors.affiliation: Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thycaud PO, Poojappura, Thiruvananthapuram 695014, India.
authors.forename: Khaja Mohieddin
authors.initials: KM
authors.lastname: Syed
authors.affiliation: Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thycaud PO, Poojappura, Thiruvananthapuram 695014, India.
authors.forename: Sunu
authors.initials: S
authors.lastname: Joseph
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, MSU, 333 Bostwick Ave, Grand Rapids, MI 49503, USA.
authors.forename: Ananda
authors.initials: A
authors.lastname: Mukherjee
authors.affiliation: Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thycaud PO, Poojappura, Thiruvananthapuram 695014, India.
authors.forename: Aditi
authors.initials: A
authors.lastname: Majumder
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, MSU, 333 Bostwick Ave, Grand Rapids, MI 49503, USA.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Teixeira
authors.affiliation: Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thycaud PO, Poojappura, Thiruvananthapuram 695014, India debasreedutta@rgcb.res.in.
authors.forename: Debasree
authors.identifier: 0000-0003-2745-9180
authors.initials: D
authors.lastname: Dutta
authors.affiliation: Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thycaud PO, Poojappura, Thiruvananthapuram 695014, India.
authors.forename: Madhavan Radhakrishna
authors.initials: MR
authors.lastname: Pillai
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics; D003114:Colony-Forming Units Assay; D004260:DNA Repair / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D015536:Down-Regulation / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D056488:Histone Chaperones / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D008239:Lysine / Q000378:metabolism; D008297:Male; D008648:Mesoderm / Q000166:cytology; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D000075223:Poly-ADP-Ribose Binding Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D015820:Cadherins; D002352:Carrier Proteins; D056488:Histone Chaperones; D006657:Histones; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D000075223:Poly-ADP-Ribose Binding Proteins; C555924:APLF protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D008239:Lysine
keywords: APLF; Histone chaperone; Histone modification; MET; MacroH2A.1; iPSCs