Investigation of chromatin remodelling in balanced X-autosome translocations and its influence on phenotype

• Grant number: 16/22860-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2017
• End date: August 31, 2020
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Maria Isabel de Souza Aranha Melaragno
• Grantee: Adriana di Battista
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 14/11572-8 - Chromosomal rearrangements and their relevance in the etiology of genetic disorders: cytogenomic and molecular investigation, AP.TEM
• Associated scholarship(s): 17/20847-9 - Investigation of chromatin reorganization in balanced X-autosome translocations, BE.EP.DR

Abstract

The three-dimensional organization of chromatin within the interphasic nucleus and how it influences gene regulation has been the subject of studies by several research groups around the world. The study of patients with phenotypic alterations and balanced chromosome translocations whose breakpoints do not break genes can help elucidate the effect of the repositioning of chromosomal segments in gene expression regulation. Literature reports show a strong association between premature ovarian failure and balanced X-autosome translocations with breakpoints between Xq13 and Xq21, although the pathogenic mechanism that affects ovarian development in these patients has not been elucidated yet. Gene disruptions caused by translocations have not been able to explain the cause of ovarian failure in the vast majority of cases. In addition, women with Xq21 deletions are generally fertile, so that ovarian failure should not be due to changes in the number of functional copies of genes in that region. Thus, the position effect is the main hypothesis to explain the genetic mechanism responsible for ovary failure in women with X-autosome translocation. This project proposes the investigation of the three-dimensional structure of chromatin and its effect on gene expression in patients with balanced X-autosomes translocations and premature ovarian failure, an innovative approach that has not yet been tested in this group of patients. This study will allow a detailed investigation of how chromatin reorganizes within the interphasic nucleus when subjected to drastic transpositions of the genomic material, as occurs in translocations. This project aims to study changes in chromatin organization that are influencing the overall gene expression in the ovarian tissue of these patients, and the results obtained may provide a better understanding of the complex mechanism of gene regulation related to the organization of the chromosomes in the interphasic nucleus. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DI-BATTISTA, A.; MOYSES-OLIVEIRA, M.; CABRAL, V.; CHRISTOFOLINI, D.; KAO, C.; MAFRA, F.; GONZALEZ, M.; PELLEGRINO, R.; REYMOND, A.; HAKONARSON, H.; et al. Complex chromosomal rearrangement associated to premature ovarian failure. European Journal of Human Genetics, v. 27, p. 2-pg., 2019-07-01. (16/22860-0)