Single-cell RNA-seq identifies a reversible epithelial-mesenchymal transition in abnormally specified epithelia of p63 EEC syndrome

Background: Monoamine neurotransmitter abundance affects motor control, emotion, and cognitive function and is regulated by monoamine oxidases. Amongst these, monoamine oxidase A (MAOA) catalyzes the degradation of dopamine, norepinephrine, and serotonin into their inactive metabolites. Loss-of-function mutations in the X-linked MAOA gene cause Brunner syndrome, which is characterized by various forms of impulsivity, maladaptive externalizing behavior, and mild intellectual disability. Impaired MAOA activity in individuals with Brunner syndrome results in bioamine aberration, but it is currently unknown how this affects neuronal function. Methods: We generated human induced pluripotent stem cell (hiPSC)-derived dopaminergic (DA) neurons from three individuals with Brunner syndrome carrying different mutations, and used CRISPR/Cas9 mediated homologous recombination to rescue MAOA function. We used these lines to characterize morphological and functional properties of DA neuronal cultures at the single cell and neuronal network level in vitro. Results: Brunner syndrome DA neurons showed reduced synaptic density but hyperactive network activity. Intrinsic functional properties and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission were not affected by MAOA dysfunction. Instead, we show that the neuronal network hyperactivity is mediated by upregulation of the GRIN2A and GRIN2B subunits of the N-methyl-D-aspartate receptor (NMDAR), and rescue of MAOA results in normalization of NMDAR function as well as restoration of network activity. Conclusions: Our data suggest that MAOA dysfunction in Brunner syndrome increases activity of dopaminergic neurons through upregulation of NMDAR function, which may contribute to Brunner syndrome associated phenotypes.

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p63 cooperates with CTCF to modulate chromatin architecture in skin keratinocytes

Zhou

2019

Preprint

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1The transcription factor p63 regulates epidermal genes and the enhancer landscape in skin 2 keratinocytes. Its molecular function in controlling the chromatin structure is however not yet 3 completely understood. Here we integrated multi-omics profiles, including the transcriptome, 4 transcription factor DNA-binding and chromatin accessibility, in skin keratinocytes isolated from EEC 5 syndrome patients carrying p63 mutations, to examine the role of p63 in shaping the chromatin 6 architecture. We found decreased chromatin accessibility in p63-and CTCF-bound open chromatin 7 regions that potentially contributed to gene deregulation in mutant keratinocytes. Cooperation of 8 p63 and CTCF seemed to assist chromatin interactions between p63-bound enhancers and gene 9 promoters in skin keratinocytes. Our study suggests an intriguing model where cell type-specific 10 transcription factors such as p63 cooperate with the genome organizer CTCF in the three-11 dimensional chromatin space to regulate the transcription program important for the proper cell 12 identity. 13 14 15

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Single-cell RNA-seq identifies a reversible epithelial-mesenchymal transition in abnormally specified epithelia of p63 EEC syndrome

Cited by 4 publications

References 57 publications

Pluripotent Stem Cell Differentiation Toward Functional Basal Stratified Epithelial Cells

Pluripotent Stem Cell Differentiation Toward Functional Basal Stratified Epithelial Cells

Brunner syndrome associated MAOA dysfunction in human dopaminergic neurons results in NMDAR hyperfunction and increased network activity

p63 cooperates with CTCF to modulate chromatin architecture in skin keratinocytes

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