Romano, Antonella
(2017)
DNA looping, histones and DNA methylation are coupled by DNA
oxidation to modulate transcription.
[Tesi di dottorato]
| Tipologia del documento: |
Tesi di dottorato
|
| Lingua: |
English |
| Titolo: |
DNA looping, histones and DNA methylation are coupled by DNA
oxidation to modulate transcription |
| Autori: |
| Autore | Email |
|---|
| Romano, Antonella | antonellaromano.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: |
| nome | email |
|---|
| Cozzolino, Salvatore | cozzolin@unina.it |
|
| Tutor: |
| nome | email |
|---|
| 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 |
[error in script]
[error in script]
| 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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