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Characterization of the inactivation of autosomal sequences in patients with unbalanced X-autosome translocations

Grant number: 20/16422-5
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): June 01, 2021
Effective date (End): May 31, 2024
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Maria Isabel de Souza Aranha Melaragno
Grantee:Bianca Pereira Favilla
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated research grant:19/21644-0 - Impact of genetic variants on genomic stability and their effects on the phenotype, AP.TEM


Rearrangements involving the X chromosome present peculiarities due to the occurrence of a skewed X-chromosome inactivation. In unbalanced X-autosome translocations, the X-Chromosome Inactivation (XCI) is preferentially skewed towards the derivative chromosome. In rare cases of derivative chromosomes containing X-chromosome sequences, including the X-inactivation center and autosomal sequences, the spread of XCI may also affect the autosomal material attached to the X chromosome. In those cases, the XCI spread into autosomal sequences may have a phenotypical impact, depending on the genes that are subject to inactivation. There are only a few studies that have analyzed the DNA methylation and gene expression profile in those cases, but none of them compared the DNA methylation of chromosomes involved in the translocation with their normal homologous chromosomes, nor analyzed the expression of all genes involved in the translocations. In the present study, the characterization of XCI spread into autosomal sequences in patients with unbalanced X-autosome translocations will be performed through chromosomal-specific DNA methylation analysis, comparing the bisulfite sequencing methylation data of the autosomes involved in the translocation and their normal homologous chromosomes, both obtained by chromosomal microdissection, as well as allele-specific gene expression using RNA-seq. DNA elements and the organization of Topologically Associating Domains (TADs) in the autosomal regions will also be evaluated, in silico, to characterize DNA and chromatin elements that can impact the spread of XCI. Our data will provide a chromosomal-specific characterization of the XCI spread, assisting in the elucidation of the impact of chromatin and DNA elements in this process, as well as its clinical consequences. (AU)

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