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Investigation of the X-chromosome inactivation spread into autosomal regions in patients carrying unbalanced X-autosome translocations

Grant number: 18/20633-1
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): May 01, 2019
Effective date (End): February 28, 2021
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:14/11572-8 - Chromosomal rearrangements and their relevance in the etiology of genetic disorders: cytogenomic and molecular investigation, AP.TEM


X-chromosome inactivation (XCI) is a process known as dosage compensation that silences gene expression from one of females' X chromosome through the establishment of epigenetic repressive marks, such as methylation of gene promoters. Although there is a random choice of which of the X chromosomes will be inactivated in females, in cases of unbalanced rearrangements that involve the X chromosome, the rearranged chromosome is preferentially inactivated. There are rare cases of inactivation of chromosomes derived from translocations that are constituted by autosomal sequences as well as X-chromosome sequences that harbors the X-inactivation center. In such cases, there can be a spread of XCI into autosomal sequences, which directly impacts the patients' phenotype. Few studies have analyzed the methylation profile of autosomal sequences in those cases and none of them could determine the methylation of chromosomes involved in the translocation by comparing them to their homologous normal chromosomes. In the present study, we will investigate XCI pattern and its spread into autosomal sequences in patients carrying unbalanced X-autosome translocations. By performing microdissection and bisulfite-sequencing of those chromosomes, we aim to identify, precisely, differentially methylated genes in order to characterize XCI spread. We will also evaluate, in silico, DNA elements and topologically associating domains (TADs) within the autosomal regions that could impact the X-inactivation spread into them. The spreading data and the function of differentially methylated genes will be correlated to the patients' phenotype, helping us to elucidate the clinical consequences and the role of DNA elements in this process. (AU)

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