Autism risk gene POGZ promotes chromatin accessibility and expression of clustered synaptic genes

Markenscoff-Papadimitriou, Eirene; Binyameen, Fadya; Whalen, Sean; Price, James D.; Lim, Kenneth J.; Ypsilanti, Athéna R.; Catta-Preta, Rinaldo; Pai, Emily Ling-Lin; Mu, Xin; Xu, Dehong; Pollard, Katherine S.; Nord, A.; State, Matthew W.; Rubenstein, John L.R.

doi:10.1016/j.celrep.2021.110089

Cited by 43 publications

(34 citation statements)

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“…POGZ has been shown to be associated with transcription repression and regulation of heterochromatin, as it is a reader of heterochromatin marks H3K9me2/3, interacts with heterochromatin protein HP1, and inhibits transcription by an in vitro luciferase assay [ 1 – 3 ]. In mouse brain tissues, POGZ forms a complex with HP1 and ADNP, members of a recently reported ChAHP repressive complex [ 15 , 34 ]. In a previous LC–MS/MS assay, POGZ was identified as a candidate interactor for HP1 and CHD4.…”

Section: Discussionmentioning

confidence: 99%

“…We propose that the major role of POGZ is involved in enhancer regulation at local euchromatin loci, likely modulating neural genes. However, POGZ is also co-localized with members of ChAHP complex and linked with heterochromatin marks such as H3K9me3/H4K20me3, suggesting that its role in these loci might be linked with gene repression [ 15 ]. The underlying mechanisms await further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…In mice, Pogz mRNA is abundantly expressed during early gestation and reaches its maximum expression on embryonic day (E) 9.5. Specifically, Pogz is broadly expressed in the developing cortex [ 14 , 15 ]. Pogz−/− mice are early embryonic lethal, and Pogz−/− embryos are absorbed as early as E10.5 when neurogenesis begins.…”

Section: Introductionmentioning

confidence: 99%

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Autism-associated protein POGZ controls ESCs and ESC neural induction by association with esBAF

2022

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Background The POGZ gene has been found frequently mutated in neurodevelopmental disorders (NDDs), particularly autism spectrum disorder (ASD) and intellectual disability (ID). However, little is known about its roles in embryonic stem cells (ESCs), neural development and diseases. Methods We generated Pogz−/− ESCs and directed ESC differentiation toward a neural fate. We performed biochemistry, ChIP-seq, ATAC-seq, and bioinformatics analyses to understand the role of POGZ. Results We show that POGZ is required for the maintenance of ESC identity and the up-regulation of neural genes during ESC differentiation toward a neural fate. Genome-wide binding analysis shows that POGZ is primarily localized to gene promoter and enhancer regions. POGZ functions as both a transcriptional activator and repressor, and its loss leads to deregulation of differentiation genes, including neural genes. POGZ physically associates with the SWI-SNF (esBAF) chromatin remodeler complex, and together they modulate enhancer activities via epigenetic modifications such as chromatin remodeling and histone modification. During ESC neural induction, POGZ-mediated recruitment of esBAF/BRG1 and H3K27ac are important for proper expression of neural progenitor genes. Limitations The genotype and allele relevant to human neurodevelopmental disorders is heterozygous loss of function. This work is designed to study the effects of loss of POGZ function on ESCs and during ESC neural induction. Also, this work lacks of in vivo validation using animal models. Conclusions The data suggest that POGZ is both a transcription factor and a genome regulator, and its loss leads to defects in neural induction and neurogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Autism-associated protein POGZ controls ESCs and ESC neural induction by association with esBAF

2022

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“…To date, only the function of HPZ (NMD-affected), CENBP and DDE domains (NMD-escaping) has been investigated. HPZ was proved to be essential for the chromatin binding and its variants abolished the interactions with HP1α [ 1 ], thus impairing the chromatin accessibility and gene expressions [ 3 ]. Variants in CENBP domain impaired the nuclear localization of POGZ protein, disrupted its DNA-binding activity, impaired cortical differentiation and increased the activity of excitatory cortical neurons in mice [ 2 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…POGZ also interacts with SP1 transcription factor and chromodomain helicase DNA-binding protein 4, which suggests that POGZ functions as a chromatin regulator, and thus is important for the normal mitotic progression, especially during cortical development [ 2 ]. Analyses of pogz knockout mice revealed that the POGZ protein promotes chromatin accessibility and expression of clustered synapse genes, and co-occupies loci with ADNP , a gene associated with autism [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Genotype-Phenotype Comparison in POGZ-Related Neurodevelopmental Disorders by Using Clinical Scoring

Nagy

Verheyen

Wigby

et al. 2022

Genes

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POGZ-related disorders (also known as White-Sutton syndrome) encompass a wide range of neurocognitive abnormalities and other accompanying anomalies. Disease severity varies widely among POGZ patients and studies investigating genotype-phenotype association are scarce. Therefore, our aim was to collect data on previously unreported POGZ patients and perform a large-scale phenotype-genotype comparison from published data. Overall, 117 POGZ patients′ genotype and phenotype data were included in the analysis, including 12 novel patients. A severity scoring system was developed for the comparison. Mild and severe phenotypes were compared with the types and location of the variants and the predicted presence or absence of nonsense-mediated RNA decay (NMD). Missense variants were more often associated with mild phenotypes (p = 0.0421) and truncating variants predicted to escape NMD presented with more severe phenotypes (p < 0.0001). Within this group, variants in the prolin-rich region of the POGZ protein were associated with the most severe phenotypes (p = 0.0004). Our study suggests that gain-of-function or dominant negative effect through escaping NMD and the location of the variants in the prolin-rich domain of the protein may play an important role in the severity of manifestations of POGZ–associated neurodevelopmental disorders.

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Epigenetic regulation of craniofacial development and disease

Shull,

Artinger

2023

Birth Defects Research

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BackgroundThe formation of the craniofacial complex relies on proper neural crest development. The gene regulatory networks (GRNs) and signaling pathways orchestrating this process have been extensively studied. These GRNs and signaling cascades are tightly regulated as alterations to any stage of neural crest development can lead to common congenital birth defects, including multiple syndromes affecting facial morphology as well as nonsyndromic facial defects, such as cleft lip with or without cleft palate. Epigenetic factors add a hierarchy to the regulation of transcriptional networks and influence the spatiotemporal activation or repression of specific gene regulatory cascades; however less is known about their exact mechanisms in controlling precise gene regulation.AimsIn this review, we discuss the role of epigenetic factors during neural crest development, specifically during craniofacial development and how compromised activities of these regulators contribute to congenital defects that affect the craniofacial complex.

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Autism risk gene POGZ promotes chromatin accessibility and expression of clustered synaptic genes

Cited by 43 publications

References 73 publications

Autism-associated protein POGZ controls ESCs and ESC neural induction by association with esBAF

Autism-associated protein POGZ controls ESCs and ESC neural induction by association with esBAF

Genotype-Phenotype Comparison in POGZ-Related Neurodevelopmental Disorders by Using Clinical Scoring

Epigenetic regulation of craniofacial development and disease

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