Romano, Antonella (2017) DNA looping, histones and DNA methylation are coupled by DNA oxidation to modulate transcription. [Tesi di dottorato]

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Tipologia del documento: Tesi di dottorato
Lingua: English
Titolo: DNA looping, histones and DNA methylation are coupled by DNA oxidation to modulate transcription
Autori:
AutoreEmail
Romano, Antonellaantonellaromano.87@libero.it
Data: 8 Maggio 2017
Numero di pagine: 149
Istituzione: Università degli Studi di Napoli Federico II
Dipartimento: Biologia
Dottorato: Biologia
Ciclo di dottorato: 29
Coordinatore del Corso di dottorato:
nomeemail
Cozzolino, Salvatorecozzolin@unina.it
Tutor:
nomeemail
Porcellini, Antonio[non definito]
Data: 8 Maggio 2017
Numero di pagine: 149
Parole chiave: Trancription; nuclear receptor; LSD1; oxidation
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/04 - Patologia generale
Depositato il: 08 Mag 2017 10:10
Ultima modifica: 16 Mar 2018 11:57
URI: http://www.fedoa.unina.it/id/eprint/11865
DOI: 10.6093/UNINA/FEDOA/11865

Abstract

Changes of histone methylation code, DNA hydroxymethylation and formation of chromatin loops are associated with transcription induction by nuclear hormones, but it is not known if these events are the consequence or the cause of transcription initiation. We studied the effect of activation of the retinoic acid receptor, at the RARE–promoter chromatin of CASP9 and CYP26A1 genes, and estrogen receptor !, at ERE and Poly_A of PS2, CAV1 and BCL2 genes. We found that histone H3 lysines 4 and 9 are demethylated by the lysine-speci"c demethylase, LSD1 and by the JMJ-domain containing demethylase, D2A. The action of the oxidase (LSD1) and a dioxygenase (JMJD2A) in the presence of Fe++ elicits an oxidation wave that locally oxidate the DNA, recruits the enzymes involved in base and nucleotide excision repair (BER and NER) and bring to formation of chromatin loops that juxtapose the 5' and 3' ends of induced genes. In addition we evaluated the crucial role of DNA methyltransferase 3a that work closely to OGG1 and APE1, favoring strand specific repair of oxo-dG and methylation of the complementary C preventing the accumulation of G to T mutations at regulative regions of studied genes. We suggest that coupling transcription with methylation and repair enzymes is an evolutionary strategy to reduce the mutational burden induced by DNA oxidation necessary for chromatin looping. We characterized the changes in chromatin structure, DNA methylation, the recruitment of Base Excision Repair during and after homologous DNA repair (HR) in HeLa DR-GFP cells. Repaired genes display stable but different methylation profiles. These profiles manage the levels of expression in generated recombinant populations. Our data argue that DNA methylation and chromatin remodelling induced by HR may be a source of permanent variation of gene expression in somatic cells. Finally we studied the relationship between chromatin remodeling of FOXP3 gene and immunophenotypic differentiation of human primary CD4+ T lymphocytes moreover the alterated immunosuppressive activity in autoimmune desease. We found that the induction and suppressive function of iTreg cells (induced Treg cells) tightly depended on glycolysis, which controlled FOXP3 splicing variants containing exon 2 ( FOXP3-E2) through the glycolytic enzyme enolase-1. The FOXP3-E2–related suppressive activity of iTreg cells was altered in human autoimmune diseases, including multiple sclerosis and type 1 diabetes, and was associated with impaired glycolysis and signaling via interleukin 2. This link between glycolysis and FOXP3-E2 variants via enolase-1 shows a previously unknown mechanism for controlling the induction and function of Treg cells in health and in autoimmunity.

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