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Identification of the genetic network responsible for pharyngeal apparatus morphogenesis in mice: a model for studying the 22q11.2 deletion syndrome

Grant number: 16/18376-5
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): February 10, 2017
Effective date (End): February 09, 2018
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal researcher:Maria Isabel de Souza Aranha Melaragno
Grantee:Anelisa Gollo Dantas
Supervisor abroad: Bernice Morrow
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Research place: Albert Einstein College of Medicine, United States  
Associated to the scholarship:14/26768-5 - Investigation of patients with 22q11.2 deletion syndrome: Gene expression profile and evaluation of regulatory elements., BP.DR


The 22q11.2 deletion syndrome (22q11.2DS; DiGeorge/velo-cardio-facial syndrome) is the most common genomic disorder in humans, and the patients harbors recurrent deletions of 3 and 1,5 Mb. However, there is a high phenotypic heterogeneity, even between members of the same family or monozygotic twins. Approximately 65% of affected individuals have congenital heart disease (CHD), affecting the cardiac outflow tract. Among the 44 known genes in the deleted region, TBX1, encoding a T-box transcription factor, is the strongest candidate gene for CHD in 22q11.2DS patients. The discovery of mutations in TBX1 in non-deleted patients with CHD further proves its role as a disease gene, but the basis of clinical heterogeneity in individuals with the deletion is only now beginning to be explored. The hypothesis is that haploinsufficiency of TBX1 along with genetic modifiers elsewhere in the genome explain the basis of clinical heterogeneity. This project will use mouse models of 22q11.2DS to analyze gene expression changes in the PA (pharyngeal apparatus) tissue isolated from wildtype versus Tbx1 loss of function embryos to expand the genetic network responsible for cardiac morphogenesis, previously described by Dr. Bernice Morrow's team. We will also identify open chromatin regions relevant to Tbx1 in the PA, using innovative ATAC-seq analysis. Integrating gene expression profiling with open-active chromatin data from cell populations within the mouse embryo PA will help to understand the regulation of TBX1 downstream genes and probably provide important information to infer mechanisms that are actually occurring during the mammalian embryogenesis process. Overall, this project will make new discoveries in the areas of cardiovascular development and disease. (AU)

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