Interaction of genetic and epigenetic factors in response to inflammation for the predisposition to cleft lip-palate

• Grant number: 17/11430-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2018
• End date: December 31, 2021
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Maria Rita dos Santos e Passos Bueno
• Grantee: Lucas Alvizi Cruz
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center, AP.CEPID
• Associated scholarship(s): 19/25350-0 - Investigation of pro-inflammatory effects on CDH1/E-cadherin in the Neural Crest, BE.EP.PD

Abstract

Cleft lip and/or palate (CL/P) is the most common congenital craniofacial malformation and displays a multifactorial pattern of inheritance. Despite of the many at risk loci identified for the CL/P, they do not completely explain the observed high heritability and incomplete penetrance is frequently featured in CL/P familial cases, suggesting the role of additional factors, either genetic or environmental. In this sense, epidemiological studies show a higher frequency of infections in CL/P patient's mothers. In a previous study, we demonstrate the association of epigenetic factors, as DNA methylation, in CL/P and CDH1 promoter hypermethylation in familial cases with incomplete penetrance, in which DNA methylation was significantly higher in penetrant cases acting, therefore, as a second hit. On the other hand, studies demonstrate CDH1 hypermethylation upon inflammatory activation. Thus, our hypothesis is that infection and the activation of inflammatory processes, combined to the foetus genetics, act as a common environmental factor in CL/P susceptibility via epigenetics. Our preliminary results in a cdh1 mutant zebrafish model demonstrate craniofacial phenotype in heterozygous embryos after inflammatory stimulus. Our main goal is to demonstrate the role of inflammation in combination with genetic factors in CL/P, using zebrafish and cell models as induced-pluripotent stem cells-derived neural crest cells. To achieve our goal, we propose the use of those animal and cellular models with the inflammatory induction by bacterial lipopolysaccharide and interleukins as well as the use of molecular tools for DNA methylation analysis, protein markers quantification, gene expression analysis and cellular migration assays.

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)

ALVIZI, LUCAS; NANI, DIOGO; BRITO, LUCIANO ABREU; KOBAYASHI, GERSON SHIGERU; PASSOS-BUENO, MARIA RITA; MAYOR, ROBERTO. Neural crest E-cadherin loss drives cleft lip/palate by epigenetic modulation via pro-inflammatory gene-environment interaction. NATURE COMMUNICATIONS, v. 14, n. 1, p. 14-pg., 2023-05-24. (17/11430-7, 13/08028-1)