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ZNF599 and DNMT3A coordinately control nuclear envelope organization by repression of SUN4 expression

ABSTRACT: Human-specific KRAB-ZF proteins are putative transcription factors and correlate with human cognitive and linguistic ability. The typical KRAB-ZF protein ZNF599 has been implicated in developmental delay. However, the underlying molecular mechanism is elusive. Here, we show a specific interaction of ZNF599 with DNMT3A, but not DNMT3B or DNMT1. Using CRISPR/Cas9, we generated a ZNF599-/- cell line that shows an irregular nuclear morphology with blebbings, dents and ridges. Interestingly, the irregular nuclear shape can be rescued by complement expression of wt ZNF599, but not with ZNF599 L178F, a mutant that has been described in patients with mental retardation. With transcriptome analysis by next-generation sequencing, we found several genes misregulated in ZNF599-/- cells, particularly an upregulation of SUN4, also known as SPAG4. Consistently, ectopic expression of GFP-SUN4 in wt cells shows a similar effect on nuclear morphology as observed in ZNF599-/- cells. Besides ZNF599, DNMT3A dependent DNA methylation is also required for repression of Sun4 expression as we observe an upregulation of Sun4 in murine Dnmt3a-/- cells. Thus, we conclude that ZNF599 and DNMT3A coordinately control SUN4 expression to regulate nuclear envelope organization providing a potential insight into the molecular mechanism of development delay pathology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE76129 | GEO | 2019/12/21

REPOSITORIES: GEO

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