Understanding the impact of ZBTB18 missense variation on transcription factor function in neurodevelopment and disease

Abstract

Mutations to genes that encode DNA‐binding transcription factors (TFs) underlie a broad spectrum of human neurodevelopmental disorders. Here, we highlight the pathological mechanisms arising from mutations to TF genes that influence the development of mammalian cerebral cortex neurons. Drawing on recent findings for TF genes including ZBTB18, we discuss how functional missense mutations to such genes confer non‐native gene regulatory actions in developing neurons, leading to cell‐morphological defects, neuroanatomical abnormalities during foetal brain development and functional impairment. Further, we discuss how missense variation to human TF genes documented in the general population endow quantifiable changes to transcriptional regulation, with potential cell biological effects on the temporal progression of cerebral cortex neuron development and homeostasis. We offer a systematic approach to investigate the functional impact of missense variation in brain TFs and define their direct molecular and cellular actions in foetal neurodevelopment, tissue homeostasis and disease states.

Gene dysregulation in acute HIV-1 infection – early transcriptomic analysis reveals the crucial biological functions affected

“…The genes that demonstrated the strongest negative correlation with viral load ( Supplementary Table 2 ) also have key functional overlaps. For example, PTPN13, SFMBT1, ARMCX1, ZNF10, and ZBTB18 are all involved in repression of transcription ( Huang et al., 2008 ; Nishitsuji et al., 2015 ; Liu et al., 2020 ; Heng et al., 2022 ; Xie et al., 2022 ). Downregulation of ZNF10 during high viremia is noteworthy as this protein has demonstrated functional capacity to limit HIV-1 gene expression in vitro ( Nishitsuji et al., 2015 ).…”

“…Downregulation of ZNF10 during high viremia is noteworthy as this protein has demonstrated functional capacity to limit HIV-1 gene expression in vitro ( Nishitsuji et al., 2015 ). Several negatively correlated genes, including FGF9, ARMCX1, PMP22, and ZBTB18 are involved in nervous system functions, such as glial cell growth, axon regeneration, myelin development and brain tumour suppression ( Li et al., 2013 ; Cartoni et al., 2016 ; Deng et al., 2018 ; Heng et al., 2022 ). High viral load may therefore be associated with inhibition of actors that regulate transcription and protect both the central and peripheral nervous systems.…”

Epigenomic tomography for probing spatially-defined molecular state in the brain

“…1C and 1D). Zbtb18 is involved in brain development and its mutation causes intellectual disability and epilepsy in human(Heng et al, 2022). Tbr1 regulates neuron identity and Tbr1 null mice showed severe defects in frontal cortex(Bedogni et al, 2010).…”

A Mendelian randomization study identifies proteins involved in neurodegenerative diseases

“…PLOD2 is overexpressed in fibroblasts, strengthening the current evidence for a potential role for fibroblasts in the pathogenesis of AD through remodelling of the extracellular matrix alongside amyloid plaques. 80 ZBTB18 is an essential transcription factor for embryonic cerebral cortex development; 81 it has been identified as a contributing factor to the 1q43q44 microdeletion syndrome, which is characterised by variable intellectual disability and brain malformations. 82 BLNK is involved in B cell receptor signalling; although the role of B cells in AD is not well understood, targeting B cells has been suggested to be beneficial for AD patients by delaying disease progression.…”