A study of the epigenetic enzyme Pr-set7/Set8 by researchers at Duke-NUS Medical School in Singapore has shown it to play a key role in stimulating neural stem cells (NSCs) from their quiescent state, enabling their proliferation and the generation of new neurons.
This ability of NSCs to oscillate between quiescence and proliferation, in order to maintain equilibrium between the two, is of central importance for brain development and homeostasis.
The study could help cast new light on the occurrence of neurodevelopmental disorders including autism and microcephaly, the authors reported in the February 10, 2021, edition of EMBO Reports.
The genetic causes of neurodevelopmental disorders are poorly understood and currently there is no cure for autism or microcephaly," said study leader Hongyan Wang, a professor and deputy director of the Neuroscience and Behavioral Disorders Program at Duke-NUS.
"This is the first study to show that Pr-set7/Set8 promotes neural stem cell reactivation, thereby playing an important role in brain development," Wang told BioWorld Science.
A histone lysine methyltransferase, Pr-set7/Set8 is involved in maintaining genome stability, DNA repair and cell cycle regulation, as well as turning various genes on or off.
The protein has remained largely unchanged as species have evolved, which is important, "as Pr-set7/Set8 is found in eukaryotes, including humans," noted Wang.
She and her colleagues therefore set out to understand the protein's function during brain development.
"We used fruit flies as a model in which to identify the genes involved in brain development and isolated a Pr-set7/Set8 mutant associated with defects in brain development," said Wang.
"Genetic variants of the human version of Pr-set7/Set8 are associated with neurodevelopmental disorders, with symptoms typically including intellectual disability, developmental delay, epilepsy and seizures."
Most NSCs are quiescent in adult mammalian brains, but are reactivated to generate new neurons in response to stimuli including injury, presence of nutrients or exercise.
However, NSCs gradually lose their capacity to proliferate with increasing age and in response to stress and anxiety.
Wang and her colleagues studied what happened when the gene coding for Pr-set7/Set8 was turned off in larval fruit fly brains and found that this resulted in a delay in the reactivation of NSCs from their quiescent state.
"We isolated a Pr-set7/Set8 mutant, which contained a mutation in the gene that resulted in loss of function," explained Wang.
"When NSCs lost Pr-set7/Set8 function, NSC reactivation was blocked, [due to which] NSCs were still in a quiescent stage and unable to produce the neurons that are critical for brain function."
To reactivate NSCs, Pr-set7/Set8 needed to turn on at least two genes: cyclin-dependent kinase 1 (Cdk1) and earthbound 1 (Ebd1).
The researchers found that overexpression of the proteins coded by these genes led to reactivation of NSCs, even when the Pr-set7 gene was turned off.
This demonstrates that "Cdk1 and Ebd1 function in the same genetic pathway as Pr-set7/Set8 during brain development," said Wang. Therefore, "we could potentially manipulate Cdk1 and Ebd1 in order to overcome the defects caused by Pr-set7 loss of function."
These findings show that Pr-set7/Set8 bound to the Cdk1 and Ebd1 genes to activate a signaling pathway, which reactivated NSCs from their quiescent state.
"Since Pr-set7/Set8 is conserved across species, our findings could contribute to the understanding of the roles of its mammalian counterpart in neural stem cell proliferation and its associated neurodevelopmental disorders," said Wang.
She and her team are now extrapolating these study findings in order to better understand the roles of the mammalian and human forms of Pr-set7/Set8, called SETD8 and KMT5A respectively, in brain development.
Together, "these findings suggest that the human variants on KMT5A likely cause neurodevelopmental disorders, which may facilitate future gene therapy for such disorders caused by KMT5A variants."