• ASXL3
• ASXL3‐related syndrome
• BRPS
• Bainbridge–Ropers Syndrome
• genetics
• genotype–phenotype
• intellectual disability

• Humans
• Female
• Male
• Spain/epidemiology
• Child, Preschool
• Child
• Genetic Association Studies
• Phenotype
• Intellectual Disability/genetics
• Intellectual Disability/pathology
• Mutation
• Infant
• Adolescent
• Adult
• Retrospective Studies
• Abnormalities, Multiple
• Facies
• Neurodevelopmental Disorders

• Bainbridge‐Ropers syndrome
• dental abnormalities
• developmental disorders

• ASXL3
• Bainbridge–Ropers syndrome
• intellectual disabilities
• nonsense variant
• whole exome sequencing

• clinical manifestations
• feeding difficulty
• multiple malformation
• rare genetic disease
• whole‐exome sequencing (WES)

• Humans
• Male
• Phenotype
• Female
• Infant
• Infant, Newborn
• Exome Sequencing
• Abnormalities, Multiple/genetics
• Abnormalities, Multiple/pathology

• 81571466 National Natural Science Foundation of China

• ASXL3
• Bainbridge‐Ropers syndrome
• Drosophila melanogaster
• neurodevelopmental disorder

• Child
• Humans
• Developmental Disabilities/genetics
• Transcription Factors/genetics
• Phenotype
• Syndrome
• Intellectual Disability/genetics
• Repressor Proteins/genetics
• Abnormalities, Multiple
• Facies
• Neurodevelopmental Disorders

• MR/V037307/1 Medical Research Council

• Humans
• Ubiquitination
• Animals
• Histones/metabolism
• Histones/genetics
• Polycomb-Group Proteins/genetics
• Polycomb-Group Proteins/metabolism
• Epigenesis, Genetic
• Disease Models, Animal

• R01AWD010411 NIH HHS
• R01NS101597 NIH HHS
• T32-GM007315 NIH HHS
• F31NS127551 NIH HHS
• T32-NS076401 NIH HHS
• T32GM007863 NIH HHS

• contstartabstract
• genome-wide association studies
• Parkinson’s disease
• depression
• genetic correlation
• genetics

• Humans
• Parkinson Disease/genetics
• Genome-Wide Association Study
• Depression/genetics
• Depression/etiology
• Mendelian Randomization Analysis
• Genetic Predisposition to Disease
• Linkage Disequilibrium
• Polymorphism, Single Nucleotide

• Animals
• Mice
• Polycomb-Group Proteins/genetics
• Polycomb-Group Proteins/metabolism
• Histones/metabolism
• Chromatin
• Polycomb Repressive Complex 1/genetics
• Polycomb Repressive Complex 1/metabolism
• Ubiquitination
• Drosophila Proteins/metabolism

• 2020ZD13 Key Research Project of Tianjin Education Commission
• 2017YFA0504102 National Key Research and Development Program
• 31970579 National Natural Science Foundation of China
• 81772676 National Natural Science Foundation of China
• 82103247 National Natural Science Foundation of China
• National Youth Talent Support Program
• 2019YFA0112100 the National Key Research and Development Project of Stem Cell and Transformation Research
• Tianjin Medical University Talent Excellence Program
• National Key Research and Development Program
• National Natural Science Foundation of China

• Development
• Epigenetics
• Genetic diseases
• Genetics
• Leukemias

• Humans
• Intellectual Disability/genetics
• Intellectual Disability/pathology
• Mutation
• Epigenesis, Genetic
• Multiomics
• Wnt Signaling Pathway/genetics
• Repressor Proteins/genetics
• Repressor Proteins/metabolism
• Transcription Factors/genetics
• Kidney Neoplasms/genetics

• DP5 OD024579 NIH HHS
• P30 CA016042 NCI NIH HHS
• T32 GM008042 NIGMS NIH HHS
• NIH
• Canadian Institutes of Health Research
• Ontario Brain Institute

• H2AK119ub1
• chromatin
• chromosomal architecture
• epigenetics
• histone modifications
• neurodevelopment
• neurodevelopmental disorders
• polycomb

• ASXL3
• Bainbridge-Ropers syndrome
• loss-of-function
• prenatal diagnosis
• whole exome sequencing

• Child, Preschool
• China
• Craniosynostoses
• Developmental Disabilities/genetics
• Female
• Humans
• Intellectual Disability/genetics
• Pregnancy
• Transcription Factors/genetics

• Shenzhen Science and Technology Innovation Commission

Small cell lung cancer (SCLC) is an aggressive disease, with patients diagnosed with either early-stage, limited stage, or extensive stage of SCLC tumor progression. Discovering and targeting the functional biomarkers for SCLC will be crucial in understanding the molecular basis underlying SCLC tumorigenesis to better assist in improving clinical treatment. Emerging studies have demonstrated that dysregulations in BAP1 histone H2A deubiquitinase complex are collectively associated with pathogenesis in human SCLC. Here, we investigated the function of the oncogenic BAP1/ASXL3/BRD4 epigenetic axis in SCLC by developing a next-generation BAP1 inhibitor, iBAP-II, and focusing on the epigenetic balance established between BAP1 and non-canonical PRC1 complexes in regulating SCLC-specific transcriptional programming. We further demonstrated that pharmacologic inhibition of BAP1’s catalytic activity disrupted BAP1/ASXL3/BRD4 epigenetic axis by inducing protein degradation of the ASXL3 scaffold protein, which bridges BRD4 and BAP1 at active enhancers. Furthermore, treatment of iBAP-II represses neuroendocrine lineage-specific ASCL1/MYCL/E2F signaling in SCLC cell lines, and dramatically inhibits SCLC cell viability and tumor growth in vivo. In summary, this study has provided mechanistic insight into the oncogenic function of BAP1 in SCLC and highlighted the potential of targeting BAP1’s activity as a novel SCLC therapy.

• BAP1
• BRCA1
• UPS
• cancer
• chromatin remodeling
• deubiquitination
• histone 2A
• intellectual disability
• neurodevelopment
• tumor
• ubiquitin
• ubiquitin-proteasome system

• Chromatin/genetics
• Epigenesis, Genetic
• Humans
• Jumonji Domain-Containing Histone Demethylases/genetics
• Methyltransferases/genetics
• Mutation
• Obsessive-Compulsive Disorder/genetics
• Transcription Factors/genetics
• Exome Sequencing

• National Natural Science Foundation of China
• Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning
• Shanghai Municipal Education Commission-Gao Feng Clinical Medicine Grant
• the grants from Shanghai Municipal Health Commission

• ASXL1
• BAP1
• BRD4
• ET domain
• ubiquitin

• ASXL3
• ASXL3-related syndrome
• BRPS
• Bainbridge-Ropers syndrome
• intellectual disability
• speech impairment

• Adolescent
• Adult
• Child
• Child, Preschool
• Developmental Disabilities/epidemiology
• Developmental Disabilities/genetics
• Developmental Disabilities/physiopathology
• Female
• Genetic Predisposition to Disease
• Genetic Variation/genetics
• Humans
• Hypertelorism/genetics
• Hypertelorism/physiopathology
• Intellectual Disability/genetics
• Intellectual Disability/physiopathology
• Male
• Muscle Hypotonia/genetics
• Muscle Hypotonia/physiopathology
• Mutation/genetics
• Neurodevelopmental Disorders/epidemiology
• Neurodevelopmental Disorders/genetics
• Neurodevelopmental Disorders/physiopathology
• Phenotype
• Transcription Factors/genetics
• Young Adult

• MR/V037307/1 Medical Research Council

Angelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay with absence of speech, happy disposition, frequent laughter, hyperactivity, stereotypies, ataxia and seizures with specific EEG abnormalities. There is a 10–15% of patients with an AS phenotype whose genetic cause remains unknown (Angelman-like syndrome, AS-like). Whole-exome sequencing (WES) was performed on a cohort of 14 patients with clinical features of AS and no molecular diagnosis. As a result, we identified 10 de novo and 1 X-linked pathogenic/likely pathogenic variants in 10 neurodevelopmental genes (SYNGAP1, VAMP2, TBL1XR1, ASXL3, SATB2, SMARCE1, SPTAN1, KCNQ3, SLC6A1 and LAS1L) and one deleterious de novo variant in a candidate gene (HSF2). Our results highlight the wide genetic heterogeneity in AS-like patients and expands the differential diagnosis.

• Adolescent
• Adult
• Angelman Syndrome/genetics
• Child
• Female
• Gene Regulatory Networks
• Genetic Association Studies
• Genetic Predisposition to Disease
• Heat-Shock Proteins
• Humans
• Infant
• Male
• Matrix Attachment Region Binding Proteins/genetics
• Receptors, Cytoplasmic and Nuclear/genetics
• Repressor Proteins/genetics
• Transcription Factors/genetics
• Vesicle-Associated Membrane Protein 2/genetics
• Exome Sequencing/methods
• Young Adult

• Instituto de Salud Carlos III
• Insitut d'Innovació i Investigació Parc Taulí I3PT
• Asociación Española de síndrome de Angelman
• Ministerio de Economía y Competitividad

The epigenetic regulator additional sex combs-like 1 (ASXL1) is an adverse prognostic factor in acute myeloid leukemia (AML). However, the mutational spectrum and prognostic factors of ASXL1-mutated (ASXL1+) AML are largely unknown. We aim to evaluate the risk factors influencing the prognosis of ASXL1+ AML.

We performed next-generation sequencing (NGS) in 1047 cases of de novo AML and discovered 91 ASXL1+ AML (8.7%). The Log-Rank test and Kaplan-Meier were used to evaluate survival rate, and the Cox regression model was used to analyze multivariate analysis.

In a total of 91 ASXL1+ AML, 86% had one or more co-mutations. The factors that had adverse impact on overall survival (OS) and event-free survival (EFS) are defined as high risk factors, including age ≥ 60 years, WBC count ≥ 50 × 10⁹/L, FLT3-ITD mutations, RUNX1 mutations, and absence of AML1-ETO fusion gene. ASXL1 mutations without any risk factor were classified as single-hit ASXL1+ AML; ASXL1 mutations accompanied with one of the risk factors was referred to as double-hit ASXL1+ AML; ASXL1 mutations with two or more of the risk factors were designated as triple-hit ASXL1+ AML. The combination of these risk factors had a negative influence on the prognosis of ASXL1+ AML. The median OS was not attained in single-hit ASXL1+ AML, 29.53 months in double-hit ASXL1+ AML, and 6.67 months in triple-hit ASXL1+ AML (P = 0.003). The median EFS was not attained in single-hit ASXL1+ AML, 29.53 months in double-hit ASXL1+ AML, and 5.47 months in triple-hit ASXL1+ AML (P = 0.002). Allogenic hematopoietic stem cell transplantation (allo-HSCT) improved the prognosis of double/triple-hit ASXL1+ AML patients.

Our study provided new insights into the mutational spectrum and prognostic factors of ASXL1+ AML patients. Our primary data suggest that the risk factors in ASXL1+ AML contribute to the poor outcome of these patients. The management of ASXL1+ AML patients should be based on the risk factors and allo-HSCT is highly recommended for consolidation.

The online version contains supplementary material available at 10.1186/s12935-021-02233-y.

• ASXL1 mutations
• Acute myeloid leukemia
• Allogenic hematopoietic stem cell transplantation
• Prognosis

• Polycomb repressive complex 1 (PRC1)
• Polycomb repressive-deubiquitinase (PR-DUB) complex
• cancer
• chromatin
• epigenetics
• neurodevelopment
• transcription

Normal function of the placenta depends on the earliest developmental stages when trophoblast cells differentiate and invade into the endometrium to establish the definitive maternal-fetal interface. Previously, we identified the ubiquitously expressed tumour suppressor BRCA1-associated protein 1 (BAP1) as a central factor of a novel molecular node controlling early mouse placentation. However, functional insights into how BAP1 regulates trophoblast biology are still missing. Using CRISPR/Cas9 knockout and overexpression technology in mouse trophoblast stem cells, here we demonstrate that the downregulation of BAP1 protein is essential to trigger epithelial-mesenchymal transition (EMT) during trophoblast differentiation associated with a gain of invasiveness. Moreover, we show that the function of BAP1 in suppressing EMT progression is dependent on the binding of BAP1 to additional sex comb-like (ASXL1/2) proteins to form the polycomb repressive deubiquitinase (PR-DUB) complex. Finally, both endogenous expression patterns and BAP1 overexpression experiments in human trophoblast stem cells suggest that the molecular function of BAP1 in regulating trophoblast differentiation and EMT progression is conserved in mice and humans. Our results reveal that the physiological modulation of BAP1 determines the invasive properties of the trophoblast, delineating a new role of the BAP1 PR-DUB complex in regulating early placentation.

• CRISPR gene editing
• developmental biology
• epithelial-mesenchymal transition
• human
• mouse
• placenta
• regenerative medicine
• stem cell self-renewal
• stem cells
• trophoblast
• trophoblast invasion

• clinical utility study
• diagnostic yield
• exome-based CNV analysis
• neurodevelopmental disorders
• trio-whole-exome sequencing

• autism
• genetics
• human pluripotent stem cells
• neural development
• prefrontal cortex

• ASXL1
• ASXL2
• ASXL3
• Bainbridge-Ropers syndrome
• Bohring-Opitz syndrome
• Shashi-Pena syndrome

• epigenetics
• biochemistry
• enzyme mechanisms

• ASXL3 mutation
• Bainbridge-Ropers syndrome
• Case report
• Whole-exome sequencing

• ASXL3
• BRPS
• Bainbridge-Ropers syndrome

Histone posttranslational modifications are key regulators of chromatin-associated processes including gene expression, DNA replication and DNA repair. Monoubiquitinated histone H2A, H2Aub (K118 in Drosophila or K119 in vertebrates) is catalyzed by the Polycomb group (PcG) repressive complex 1 (PRC1) and reversed by the PcG-repressive deubiquitinase (PR-DUB)/BAP1 complex. Here we critically assess the current knowledge regarding H2Aub deposition and removal, its crosstalk with PcG repressive complex 2 (PRC2)-mediated histone H3K27 methylation, and the recent attempts toward discovering its readers and solving its enigmatic functions. We also discuss mounting evidence of the involvement of H2A ubiquitination in human pathologies including cancer, while highlighting some knowledge gaps that remain to be addressed.

Histone H2A monoubiquitination on lysine 119 in vertebrate and lysine 118 in Drosophila (H2Aub) is an epigenomic mark usually associated with gene repression by Polycomb group factors. Here the authors review the current knowledge on the deposition and removal of H2Aub, its function in transcription and other DNA-associated processes as well as its relevance to human disease.

Polycomb group proteins are important for maintaining gene expression patterns and cell identity in metazoans. The mammalian Polycomb repressive deubiquitinase (PR-DUB) complexes catalyze removal of monoubiquitination on lysine 119 of histone H2A (H2AK119ub1) through a multiprotein core comprised of BAP1, HCFC1, FOXK1/2, and OGT in combination with either of ASXL1, 2, or 3. Mutations in PR-DUB components are frequent in cancer. However, mechanistic understanding of PR-DUB function in gene regulation is limited. Here, we show that BAP1 is dependent on the ASXL proteins and FOXK1/2 in facilitating gene activation across the genome. Although PR-DUB was previously shown to cooperate with PRC2, we observed minimal overlap and functional interaction between BAP1 and PRC2 in embryonic stem cells. Collectively, these results demonstrate that PR-DUB, by counteracting accumulation of H2AK119ub1, maintains chromatin in an optimal configuration ensuring expression of genes important for general functions such as cell metabolism and homeostasis.

• ASXL3
• BAP1 complex
• BET inhibitors
• BRD4
• Enhancer activity
• SCLC

• Basic Helix-Loop-Helix Transcription Factors/genetics
• Basic Helix-Loop-Helix Transcription Factors/metabolism
• Cell Cycle Proteins/metabolism
• Drug Discovery
• Enhancer Elements, Genetic
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Models, Biological
• Multiprotein Complexes
• Promoter Regions, Genetic
• Protein Binding
• Small Cell Lung Carcinoma/drug therapy
• Small Cell Lung Carcinoma/genetics
• Small Cell Lung Carcinoma/metabolism
• Small Cell Lung Carcinoma/pathology
• Transcription Factors/metabolism
• Transcriptional Activation
• Tumor Suppressor Proteins/metabolism
• Ubiquitin Thiolesterase/metabolism

• R50 CA221848 NCI NIH HHS
• P41 GM108569 NIGMS NIH HHS
• P30 CA060553 NCI NIH HHS
• T32 CA070085 NCI NIH HHS
• S10 OD025194 NIH HHS

Bainbridge–Ropers syndrome (BRPS) is a recently described developmental disorder caused by de novo truncating mutations in the Additional sex combs-like 3 (ASXL3) gene. Only four cases have been reported in China and are limited to the analysis of its clinical abnormalities, medical imaging features and gene variation. The aim of this study was to investigate the clinical phenotype, imaging manifestations and genetic characteristics of BPRS syndrome caused by ASXL3 gene mutation. Clinical data, medical imaging data and gene test results of BRPS in infant patients were retrospectively analyzed, and related literature was summarized.

At the age of 8 months, brain MRI showed that the subarachnoid space of the forehead was widened, part of the sulci was deepened, and the corpus callosum was thin. The development quotient (DQ) was determined using the 0~6-year-old pediatric examination table of neuropsychological development at 6 months and 8 months. The DQ of both tests was less than 69. Whole-exome sequencing revealed a heterozygous frameshift mutation c.3493_3494deTG in exon 12 of the ASXL3 gene, resulting in the amino acid change p. (Cys1165Ter). No variation was present at this site in her parents. Sanger sequencing of family members validated this analysis, suggesting a de novo mutation. The de novo ASXL3 mutations generated stop codons and were predicted, in silico, to generate a truncated ASXL3.

The main clinical features of the patient included psychomotor development retardation, difficulty in feeding, hypotonia, and special facial features. MRI features showed that brain development lagged behind that of normal children. Genetic testing is helpful in the early diagnosis of BRPS.

• ASXL3 gene
• Bainbridge–ropers syndrome
• Magnetic resonance imaging
• Psychomotor retardation
• Whole-exome sequencing

• ASXL3 protein
• Bainbridge-Ropers syndrome
• Xenopus laevis embryos
• neural crest
• neurodevelopmental disease model

De novo sequence variants, including truncating and splicing variants, in the additional sex-combs like 3 gene (ASXL3) have been described as the cause of Bainbridge-Ropers syndrome (BRS). This pathology is characterized by delayed psychomotor development, severe intellectual disability, growth delay, hypotonia and facial dimorphism. The present study reports a case of a girl (born in 2013) with severe global developmental delay, central hypotonia, microcephaly and poor speech. The proband was examined using a multi-step molecular diagnostics algorithm, including karyotype and array-comparative genomic hybridization analysis, with negative results. Therefore, the proband and her unaffected parents were enrolled for a pilot study using targeted next-generation sequencing technology (NGS) with gene panel ClearSeq Inherited Disease^XT and subsequent validation by Sanger sequencing. A novel de novo heterozygous frameshift variant in the ASXL3 gene (c.3006delT, p.R1004Efs*21), predicted to result in a premature termination codon, was identified. In conclusion, the present study demonstrated that targeted NGS using a suitable, gene-rich panel may provide a conclusive molecular genetics diagnosis in children with severe global developmental delays.