Epigenetic reversal of haploinsufficiency of TCF4, a gene involved in Pitt-Hopkins syndrome, a neglected neurological childhood disease

• Grant number: 18/03613-7
• Support Opportunities: Scholarships in Brazil - Master
• Start date: June 01, 2018
• End date: February 29, 2020
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Fabio Papes
• Grantee: José Ricardo Teixeira Júnior
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Pitt-Hopkins Syndrome (PTHS) is a rare neglected neurological childhood disease, characterized by intellectual disability, absence of language, developmental delay, and a characteristic facial gestalt. PTHS is caused by haploinsufficiency of the TCF4 gene, which codes for a transcription factor shown to be involved in regulating proliferation and differentiation of neural progenitor cells. The mechanisms by which TCF4 haploinsufficiency results in PTHS are still elusive. Specifically, it is not clear whether the debilitating symptoms of PTHS results from functional deficits during CNS development or when it is completely formed. Moreover, it is also not clear whether a subset of TCF4 target genes or a large-scale transcriptional change underlie the pathological characteristics of the syndrome. At the moment, there is renewed interest in gene therapy due to recent highly successful clinical trials. Therefore, the use of correctional therapies to reverse TCF4 haploinsufficiency by increasing the expression of the normal allele became a real possibility. In this project, we will design and test a system to promote targeted TCF4 epigenetic activation through the use of the CRISPR/Cas9 tool. This system will allow us to better understand TCF4 molecular biology and may provide the starting point for the development of future correctional therapy in PTHS children. (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)

PAPES, FABIO; CAMARGO, ANTONIO P.; DE SOUZA, JANAINA S.; CARVALHO, VINICIUS M. A.; SZETO, RYAN A.; LAMONTAGNE, ERIN; TEIXEIRA, JOSE R.; AVANSINI, SIMONI H.; SANCHEZ-SANCHEZ, SANDRA M.; NAKAHARA, THIAGO S.; et al. Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content. NATURE COMMUNICATIONS, v. 13, n. 1, p. 26-pg., 2022-05-02. (20/11451-7, 18/04240-0, 18/03613-7)

TEIXEIRA, JOSE R.; SZETO, RYAN A.; CARVALHO, VINICIUS M. A.; MUOTRI, ALYSSON R.; PAPES, FABIO. Transcription factor 4 and its association with psychiatric disorders. TRANSLATIONAL PSYCHIATRY, v. 11, n. 1, JAN 5 2021. (18/03613-7, 20/11451-7)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

TEIXEIRA JÚNIOR, José Ricardo. Epigenetic reversal of haploinsufficiency of TCF4, a gene involved in Pitt-Hopkins syndrome, a neglected neurological childhood disease. 2020. Master's Dissertation - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.