Histone H3K36 methyltransferases NSD1 and SETD2 are required for brain development

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Genetic variants in histone H3K36 methyltransferases NSD1 and SETD2 are associated with neurodevelopmental disorders.
• Understanding the precise roles of these enzymes in brain development is crucial for identifying disease mechanisms.

Purpose of the Study:

• To investigate the genetic basis of disease-relevant variants in NSD1 and SETD2.
• To explore the genotype-phenotype correlations in patients with these variants.
• To elucidate the functions of Nsd1 and Setd2 in mammalian brain development.

Main Methods:

• Analysis of publicly available patient cohorts for genotype-phenotype correlations.
• Generation of mouse models with conditional knockout of Nsd1 and Setd2 in neuroepithelial cells (Sox1-cre).

Main Results:

• Conditional Nsd1 knockout mice displayed reduced brain size and neocortical thinning.
• Conditional Setd2 knockout resulted in neonatal lethality, characterized by intracerebral hemorrhage and vascular abnormalities.

Conclusions:

• Nsd1 and Setd2 play critical, distinct roles in mammalian brain development.
• These findings highlight the importance of histone methylation in neurodevelopmental processes.