Using patient derived induced-pluripotent stem cells (iPSC) to define the role of pathogenic DNMT3A mutations in Tatton-Brown-Rahman Syndrome (TBRS)

Serge McGraw, PhD
Associate Professor
Department of Obstetrics and Gynecology
Faculty of Medicine, Université de Montréal

Researcher
CHU Ste-Justine Research Centre 

This conference is hosted by Mohan Malleshaiah, PhD. This conference is part of the 2022-2023 IRCM conference calendar.

In person: 
IRCM Auditorium
110, avenue des Pins O, H2W 1R7 Montreal

Online:
Zoom Link : https://zoom.us/j/95269762104
ID : 952 6976 2104
Code : 476372

IRCM conferences are set to occur under a hybrid format. However, please note that last-minute changes to online-only lectures may occur due to unforeseen circumstances. We invite you to visit this webpage again a few days before attending.

About this conference
Rare germline heterozygous mutations in functional DNMT3A (DNA methyltransferase 3A) domains cause an overgrowth intellectual disability syndrome called Tatton-Brown-Rahman Syndrome (TBRS). DNMT3A is essential for establishing DNA methylation marks, epigenetic modifications implicated in gene regulation and genome stability, that are crucial to establish and maintain proper cellular identity. We remain unaware of how pathogenic sequence variants in human DNMT3A contribute to alterations in molecular and cellular processes at the origin of the neurodevelopmental disorders observed in TBRS patients.

Using cells from two TBRS patients carrying different single mutations in the methyltransferase domain of DNMT3A (DNMT3A^+/mut), as well as control patients (DNMT3A^+/+), we generated induced-pluripotent stem cells (iPSC), derived these cells into neuronal progenitor cells (NPC) and terminally differentiated neurons to uncover the impacts of pathogenic DNMT3A haploinsufficiency during brain cell development. We show that DNA methylation and gene expression alterations present in DNMT3A^+/mut iPSC are exacerbated during the progression into NPC. A significant number of these alterations are conserved between mutations, pointing towards common pathways targeted by the PRC2 repressive complex (Polycomb 2 repressive complex). When we further differentiate DNMT3A^+/mut into cortical neurons, the neurons show significant derepression of PRC2-target genes as well as key regulators (e.g., NEUROD1, FOXJ1, PAX6, PAX7) of brain development and cell fate commitment.

Our data suggest that, as TBRS-derived pluripotent cells undergo cellular differentiation and lineage commitment, the negative impact of pathogenic DNMT3A mutations on the distribution of DNA methylation marks and gene expression profiles intensifies, thus potentially altering cell fate and contributing to the developmental outcomes observed in TBRS patients.

About Serge McGraw
Dr. Serge McGraw is an Associate Professor in the Department of Obstetrics and Gynecology at the Université de Montréal. He completed his PhD at Laval University (Quebec) and a postdoctoral fellowship at McGill University (Montreal), where he developed an expertise in Developmental Biology and Epigenetics. He holds a Junior 2 Research Scholar award from FRQS, as well as various research grants from funding agencies (e.g. CIHR, NSERC). Combining in vitro patient-derived stem cell models and in vivo mouse models with multi-omics and bioinformatics sequencing approaches, his main research interests aim to understand how perturbations in the embryonic epigenetic program can alter cell fate and lead to abnormal development and neurodevelopmental disorders.

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