Cirino, Andrea (2018) TBX1 Transcription Factor: mechanisms of gene regulation. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Resource language: English
Title: TBX1 Transcription Factor: mechanisms of gene regulation
Creators:
CreatorsEmail
Cirino, Andreaandreacirino@ymail.com
Date: 7 December 2018
Number of Pages: 90
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Dottorato: Medicina molecolare e biotecnologie mediche
Ciclo di dottorato: 31
Coordinatore del Corso di dottorato:
nomeemail
Avvedimento, Vittorio Enricoavvedim@unina.it
Tutor:
nomeemail
Baldini, AntonioUNSPECIFIED
Date: 7 December 2018
Number of Pages: 90
Keywords: TBX1, Chromatin, ATAC-seq
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/11 - Biologia molecolare
Date Deposited: 09 Jan 2019 13:15
Last Modified: 27 Jun 2020 05:11
URI: http://www.fedoa.unina.it/id/eprint/12507

Collection description

The Tbx1 gene encodes a transcription factor, TBX1, critical for heart development in several species, including humans. The haploinsufficiency of this gene is associated with DiGeorge Syndrome (DGS) named also 22q11.2 Deletion Syndrome (22q11.2DS) which is characterized by multiple congenital anomalies, including heart disease (CHD). The molecular mechanisms by which TBX1 regulates its targets are unclear. In my thesis work I have focused on chromatin interactions mechanisms. In a first set of experiments using as a model a specific target gene, I have demonstrated that loss of TBX1 correlate with acetylation of a specific enhancer named anterior Heart Field (AHF) of the Mef2c gene, a gene critical for cardiogenesis. The mechanisms by which TBX1 affects histone acetylation need to be clarified, but we could not demonstrate a direct interaction with HDAC1 and HDAC2. Most of my thesis work has been dedicated to understanding the role of TBX1 in chromatin remodelling. By manipulation of two different model systems, I have generated maps of the accessible regions in different dosages of Tbx1. In P19Cl6 cells, I found that 86% of TBX1 binding sites are in closed chromatin. After Tbx1 knock down, I found that differentially accessible regions (DARs) are not localized in regions bound by TBX1. Consistent with this finding, I did not find T-box motifs in DARs. However, a limited study using time-course experiments identified a delayed chromatin remodelling in selected loci bound by TBX1. In contrast, a study of chromatin remodelling in differentiated murine embryonic stem cells (mESCs), WT and Tbx1-/- revealed that DARs do have T-box motifs suggesting that a good portion of chromatin changes may be located in TBX1-binding regions. Comparison between P19Cl6 and mESCs reveals differences about DARs binding motifs and communalities about the increase numbers of accessible regions after Tbx1 loss of function. In conclusion, my studies revealed new insight into the mechanisms by which TBX1 affects the chromatin landscape and indicate that mechanisms may be different depending on the cellular context.

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