Overexpression of H3K36 methyltransferase NSD in glial cells affects brain development in Drosophila

Abstract

NSD1 is a histone methyltransferase that methylates the lysine 36 at histone H3. NSD duplication is associated with short stature, microcephaly, intellectual disability, and behavioral defects in humans. Ectopic overexpression of NSD, an NSD1 homolog in Drosophila, was shown to induce developmental abnormalities via apoptosis. In this study, to investigate the effects of NSD overexpression on Drosophila brain development, we first examined the typical NSD expression pattern in larval brains and found that endogenous NSD promoter activity was detected only in subsets of glial cells. Pan-glial, but not panneuronal, NSD overexpression induced apoptosis in larval brain cells. However, pan-glial NSD overexpression also induced caspase-3 cleavage in neuronal cells. Among the various glial cell types, NSD overexpression in only astrocytic glia induced apoptosis and abnormal learning defects in the larval stage. Furthermore, NSD overexpression downregulated the expression of various astrocyte-specific genes, including draper (drpr), possibly owing to an indirect effect of NSD overexpression-induced astrocytic apoptosis. Since drpr plays a role in axon pruning during mushroom body (MB) formation in Drosophila astrocytes, we examined the effect of astrocytic NSD overexpression on this process and found that it disrupted the clearance of γ-neurons in the MB, subsequently inducing arrhythmic locomotor activity of the fly. Thus, these results suggest that aberrant NSD overexpression may cause neurodevelopmental disorders by interfering with crucial functions of astrocytes in the brain, underlining the importance of the tightly controlled astrocytic NSD expression for proper neurodevelopment.

Drosophila Glia: Models for Human Neurodevelopmental and Neurodegenerative Disorders

“…Interestingly, NSD overexpression in glial cells, not neurons, induces brain cell death, behavioral defects, and a decrease in brain size that is similar to the microcephaly phenotype of patients with NSD1 duplication. Among glial subtypes, the dysfunction of astrocyte-like glia appears to be the main cause of the NSD overexpression phenotypes that accompany learning disabilities and abnormal circadian rhythms [141]. These results from Drosophila suggest that the human NSD1 duplication disease may be caused by astrocyte dysfunction.…”

Histone modification: Biomarkers and potential therapies in colorectal cancer

“…The KMT2 family is a SET1 ‐related protein complex with H3K4 substrates, such as KMT2D , that promotes transcriptional activity. The majority of KMT3 substrates, including nuclear receptor binding SET1 domain NSD1, NSD2 , and NSD3 , and NSD overexpression predisposes cells to apoptosis (Kim et al., 2020). The KMT4 family has only DOT1L that acts on H3K79; the KMT5 family has PR‐Set7 and SUV4‐20H1/2 with substrates in histone H4 lysine 20; the KMT6 family has enhancer of zeste 1 polycomb repressive complex 2 subunit EZH1 and EZH2 , which act on histone H3 on lysine 27.…”

Structural and functional specificity of H3K36 methylation

“…This phenotype was recapitulated by deletion of an NSD1 -like gene in fly, with developmental symptoms accompanied by global H3K36me2 reduction, defective motor and memory functions, and body size overgrowth [ 133 ]. Conversely, overexpression of the NSD1 homolog induced neuronal apoptosis and larval locomotive defects [ 134 ].…”