The gain-of-function UBE3AQ588E variant causes Angelman-like neurodevelopmental phenotypes in mice DOI Creative Commons

Kellan P. Weston,

Anna M. Gunelson,

Susan E. Maloney

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 17, 2025

Mutations in the E3 ubiquitin ligase UBE3A that cause enzymatic gain-of-function result disease phenotypes which differ from classic Angelman syndrome. However, these are highly heterogeneous raising questions about mechanistic basis of such phenotypic diversity. Here, we characterize a mouse model harboring Ube3aQ606E gain function variant (UBE3AQ588E humans). Extensive behavioral phenotyping showed animals possessing maternally inherited mutation (Ube3amQ606E) paradoxically show many deficits indicative overall loss-of-function. These included pronounced motor deficits, hypoactivity, and reduced stereotypic behaviors. Moreover, brain weights MRI analysis revealed global microcephaly with postnatal onset, consistent described syndrome mice. Additional biochemical analyses demonstrated an increased abundance substrates tissue immunofluorescence is not caused by apoptotic cell death. Together, our results strongly suggest novel mechanism Ube3amQ606E leads to enhanced self-targeted degradation UBE3A, leading loss enzyme activity, resulting Angelman-like vivo.

Language: Английский

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective DOI Creative Commons
Britt Mossink, Moritz Negwer, Dirk Schubert

et al.

Cellular and Molecular Life Sciences, Journal Year: 2020, Volume and Issue: 78(6), P. 2517 - 2563

Published: Dec. 2, 2020

Abstract Neurodevelopmental disorders (NDDs), including intellectual disability (ID) and autism spectrum (ASD), are a large group of in which early insults during brain development result wide heterogeneous clinical diagnoses. Mutations genes coding for chromatin remodelers overrepresented NDD cohorts, pointing towards epigenetics as convergent pathogenic pathway between these disorders. In this review we detail the role NDD-associated developmental continuum progenitor expansion, differentiation, cell-type specification, migration maturation. We discuss how defects remodelling time points compound over impaired circuit establishment. particular, focus on their three largest cell populations: glutamatergic neurons, GABAergic glia cells. An in-depth understanding spatiotemporal neurodevelopment can contribute to identification molecular targets treatment strategies.

Language: Английский

Citations

80
Epigenetic regulation of energy metabolism in obesity DOI Creative Commons
Wei Gao, Jiali Liu, Xiang Lü

et al.

Journal of Molecular Cell Biology, Journal Year: 2021, Volume and Issue: 13(7), P. 480 - 499

Published: July 1, 2021

Obesity has reached epidemic proportions globally. Although modern adoption of a sedentary lifestyle coupled with energy-dense nutrition is considered to be the main cause obesity epidemic, genetic preposition contributes significantly imbalanced energy metabolism in obesity. However, variants loci identified from large-scale studies do not appear fully explain rapid increase last four five decades. Recent advancements next-generation sequencing technologies and tissue-specific effects epigenetic factors metabolic organs have advanced our understanding regulation The epigenome, including DNA methylation, histone modifications, RNA-mediated processes, characterized as mitotically or meiotically heritable changes gene function without alteration sequence. Importantly, modifications are reversible. Therefore, comprehensively landscape could unravel novel molecular targets for treatment. In this review, we summarize current knowledge on roles such methylation acetylation, processes regulating metabolism. We also discuss therapeutic agents

Language: Английский

Citations

61
The disordered N-terminal domain of DNMT3A recognizes H2AK119ub and is required for postnatal development DOI

Tianpeng Gu,

Dapeng Hao, Junsung Woo

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(5), P. 625 - 636

Published: May 1, 2022

Language: Английский

Citations

50
Identification of selective SWI/SNF dependencies in enzalutamide-resistant prostate cancer DOI Creative Commons
Bengul Gokbayrak, Umut Berkay Altıntaş, Shreyas Lingadahalli

et al.

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: Feb. 4, 2025

Enzalutamide is a potent second-generation antiandrogen commonly used to treat hormone-sensitive and castration-resistant prostate cancer (CRPC) patients. While initially effective, the disease almost always develops resistance. Given that many enzalutamide-resistant tumors lack specific somatic mutations, there strong evidence epigenetic factors can cause enzalutamide To explore how resistance arises, we systematically test all modifiers in several models of with custom CRISPR library. From this, identify validate SMARCC2, core component SWI/SNF complex, selectivity essential models. We show chromatin occupancy SMARCC2 BRG1 expanded at regions overlap CRPC-associated transcription are accessible CRPC clinical samples. Overall, our study reveals regulatory role for supports feasibility targeting complex late-stage PCa. An epigenome-focused screen identified unique dependency against complexes potentially mediated by an expansion their binding regions.

Language: Английский

Citations

1
Single-cell technology grows up: Leveraging high-resolution omics approaches to understand neurodevelopmental disorders DOI Creative Commons
Joseph D. Dougherty, Simona Sarafinovska, Sneha Chaturvedi

et al.

Current Opinion in Neurobiology, Journal Year: 2025, Volume and Issue: 92, P. 102990 - 102990

Published: March 3, 2025

Language: Английский

Citations

1
MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion DOI
Abdulkhaleg Ibrahim, Christophe Papin,

Kareem Mohideen-Abdul

et al.

Science, Journal Year: 2021, Volume and Issue: 372(6549)

Published: June 25, 2021

MeCP2 binds hydroxymethylated CA repeats Despites of decades research on the Rett syndrome protein MeCP2, its function remains unclear. Ibrahim et al. show that is a cytosine-adenosine (CA) repeat-binding modulates chromatin architecture at distance from transcription start site (see Perspective by Zhou and Zoghbi). accumulates spreads around modified competes for nucleosome occupancy. Loss results in widespread increase density inside lamina-associated domains transcriptional dysregulation genes enriched repeats. These shed light underlying molecular mechanism syndrome, severe disease associated with mutations MeCP2. Science , abd5581, this issue p. eabd5581 ; see also abj5027, 1390

Language: Английский

Citations

50
MicroRNAs in the Onset of Schizophrenia DOI Creative Commons

Kristen T. Thomas,

Stanislav S. Zakharenko

Cells, Journal Year: 2021, Volume and Issue: 10(10), P. 2679 - 2679

Published: Oct. 6, 2021

Mounting evidence implicates microRNAs (miRNAs) in the pathology of schizophrenia. These small noncoding RNAs bind to mRNAs containing complementary sequences and promote their degradation and/or inhibit protein synthesis. A single miRNA may have hundreds targets, targets are overrepresented among schizophrenia-risk genes. Although schizophrenia is a neurodevelopmental disorder, symptoms usually do not appear until adolescence, most patients receive diagnosis late adolescence or early adulthood. However, few studies examined miRNAs during this critical period. First, we examine that pathway dynamic throughout adulthood regulate processes neurodevelopment aberrant with Next, implicating conversion psychosis, including schizophrenia-associated nucleotide polymorphism MIR137HG strongest known predictors age onset Finally, how hemizygosity for DGCR8, which encodes an obligate component complex synthesizes precursors, contribute psychosis 22q11.2 microdeletions animal models disorder can help us understand many roles

Language: Английский

Citations

42
NSD1 deposits histone H3 lysine 36 dimethylation to pattern non-CG DNA methylation in neurons DOI Creative Commons
Nicole Hamagami, Dennis Y. Wu,

Adam W. Clemens

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(9), P. 1412 - 1428.e7

Published: April 24, 2023

Language: Английский

Citations

23
Dissecting the Relationship Between Neuropsychiatric and Neurodegenerative Disorders DOI

Rohan Gupta,

Dia Advani, Divya Yadav

et al.

Molecular Neurobiology, Journal Year: 2023, Volume and Issue: 60(11), P. 6476 - 6529

Published: July 17, 2023

Language: Английский

Citations

23
Rare diseases of epigenetic origin: Challenges and opportunities DOI Creative Commons
Maggie P. Fu, Sarah M. Merrill, Mehul Sharma

et al.

Frontiers in Genetics, Journal Year: 2023, Volume and Issue: 14

Published: Feb. 6, 2023

Rare diseases (RDs), more than 80% of which have a genetic origin, collectively affect approximately 350 million people worldwide. Progress in next-generation sequencing technology has both greatly accelerated the pace discovery novel RDs and provided accurate means for their diagnosis. that are driven by altered epigenetic regulation with an underlying basis referred to as rare origin (RDEOs). These pose unique challenges research, they often show complex clinical heterogeneity arising from unknown gene-disease mechanisms. Furthermore, multiple other factors, including cell type developmental time point, can confound attempts deconvolute pathophysiology these disorders. further exacerbated factors contribute variability difficulty collecting sufficient participant numbers human studies. However, new molecular bioinformatics techniques will provide insight into how disorders manifest over time. This review highlights recent studies addressing innovative solutions. Further research elucidate mechanisms action RDEOs facilitate treatments diagnostic biomarkers screening, thereby improving health trajectories outcomes affected patients.

Language: Английский

Citations

21