Investigation of the effect of YY1 variants on the pattern of X chromosome inactivation in women

• Grant number: 23/15506-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2024
• Status: Discontinued
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Ana Cristina Victorino Krepischi
• Grantee: Bianca Mie Sato Kurashima
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 25/04380-0 - Molecular characterization of YY1 allele-specific expression patterns in females diagnosed with Gabriele-de Vries syndrome, BE.EP.IC

Abstract

X chromosome inactivation (XCI) takes place during early stages of embryonic development in female mammals, resulting in random silencing of one of the two X chromosomes. Inactivation is initiated at the X-inactivation centre (XIC) within the future inactive X chromosome (Xi). The XIC houses, among other non-coding RNA genes, the XIST gene. The XIST transcript coats the future Xi, inducing epigenetic modifications which drive progressive chromatin condensation. The YY1 protein plays a pivotal role in this process, by acting as a transcriptional activator of the XIST gene, as a bridge that facilitates the association of XIST RNA with the chromatin of the future Xi and potentially recruiting chromatin repressive complexes. In virtue of XCI, women exhibit two cell subpopulations with distinct origins - either maternal or paternal - for the active X. The ratio of these two cell populations varies among different women and across different tissues within the same woman, ranging from 0:100 (complete skewing) to 50:50 (random inactivation). In a recent study, our research group identified a de novo pathogenic variant in the YY1 gene (Gabriele-de Vries Syndrome) associated with complete XCI skewing in a woman with syndromic intellectual disability. In light of this context, the present study aims to investigate whether potentially deleterious variants in the YY1 gene and related genes (YY2, YY1AP1, YAF2 and XIST) may modulate the XCI pattern. By analyzing whole exome sequencing data from 50 individuals with the 46,XX chromosome constitution, we will categorize variants mapped to the genes of interest (YY2, YY1AP1, YAF2 and XIST) into two groups: benign vs. potentially deleterious. The XCI pattern of the carriers of the selected variants will be assessed in peripheral blood DNA samples, based on the analysis of polymorphisms in two different X loci subject to inactivation (AR and RP2). Additionally, we intend to expand our cohort of patients bearing YY1 pathogenic variants for further collection and examination of biological material. Therefore, we hope to deepen the understanding of the effect of variants in genes directly or indirectly associated with XCI.