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

Author(s)

José Ricardo Teixeira

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2020-02-14

Examining board members

Fabio Papes; José Andrés Yunes; Mariana Maschietto; Ângela Saito

• Advisor: Fabio Papes

Abstract

Pitt-Hopkins Syndrome (PTHS) is a rare neurological disease of the infancy characterized by intellectual disability, delayed motor and speech development, dysmorphic facial features and severe constipation; the presence of other symptoms such as microcephaly, short stature, stereotypies, apneic spells, seizures, myopia and strabismus vary from patient to patient. The disease is caused by haploinsufficiency of the TCF4 gene, which encodes more than 18 different isoforms of a basic helix-loop-helix transcription factor distinctively expressed in various tissues in a spatial-temporal manner for the regulation of cell proliferation and differentiation. However, the mechanisms by which TCF4 haploinsufficiency results in PTHS are still elusive. More importantly, it is not exactly clear when and how deficits occur during brain development. Specifically, it is not clear how reduced levels of TCF4 disrupts neurogenesis and/or function and plasticity of certain subclasses of neurons. Moreover, it is unknown which TCF4 isoforms underlie the pathological characteristics of the syndrome. Finally, it is also not clear if and how TCF4 mutation spectrum explains the phenotypic variation in PTHS. To address these questions, the complex spatial-temporal expression of different TCF4 isoforms must be dealt with accordingly. Thus, we elaborated a way to endogenously modulate the expression of specific TCF4 isoforms. Combined analysis of publicly available data showed that three TCF4 isoforms originating from different transcription start sites are preferentially expressed in fetal and adult brain tissues. The use of our strategy to selectively target these transcription start sites in a human neuroblastoma cell line resulted in modulation of TCF4 expression in a transcript-specific manner. Further analysis revealed that up- or down-regulation of previously known TCF4 targets can be conditional on TCF4 isoform. These results show that our strategy can be useful as a new tool for the investigation of how TCF4 dynamics regulate complex neural processes that when disrupted lead to a pathological state. (AU)

• FAPESP's process: 18/03613-7 - Epigenetic reversal of haploinsufficiency of TCF4, a gene involved in Pitt-Hopkins syndrome, a neglected neurological childhood disease
• Grantee: José Ricardo Teixeira Júnior
• Support Opportunities: Scholarships in Brazil - Master