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
• Start date: June 01, 2021
• End date: November 30, 2025
• 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
• Associated scholarship(s): 23/01147-7 - Unveiling mechanisms mediating gene silencing and escape regulation in X-chromosome inactivation, BE.EP.DR

Abstract

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)

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)

FAVILLA, BIANCA PEREIRA; AL-RIKABI, AHMED; BRUNO, DANIELLE C. F.; ASPRINO, PAULA; MELONI, VERA AYRES; GALANTE, PEDRO A. F.; LOPES-CENDES, ISCIA; BELLUCCO, FERNANDA TEIXEIRA; LIEHR, THOMAS; MELARAGNO, MARIA ISABEL. Single-chromosome methylation sequencing and gene expression data unravel spreading of X-chromosome inactivation into gene-rich autosomal regions in an unbalanced t(X;13) translocation. European Journal of Human Genetics, v. 32, p. 1-pg., 2024-12-01. (20/16422-5)

FAVILLA, BIANCA PEREIRA; OLIVATI, CAROLINE; FREITAS, ERIKA LOPES; SANTOS, BIBIANA; MELARAGNO, MARIA ISABEL; MELONI, VERA AYRES; PIAZZON, FLAVIA BALBO. Mildly skewed X-chromosome inactivation as a mechanism for the expression of Allan-Herndon-Dudley syndrome phenotype in a female patient. European Journal of Human Genetics, v. 31, p. 1-pg., 2023-05-11. (19/21644-0, 20/16422-5)