Intellectual disability‐associated
            <scp>dBRWD</scp>
            3 regulates gene expression through inhibition of
            <scp>HIRA</scp>
            /
            <scp>YEM</scp>
            ‐mediated chromatin deposition of histone H3.3

Chen, Wei‐Yu; Shih, Hsueh‐Tzu; Liu, Kuei‐Yan; Shih, Zong‐Siou; Chen, Likai; Tsai, T. C.; Chen, Mei‐Ju; Liu, Hsuan; Tan, Bertrand Chin‐Ming; Chen, Chien‐Yu; Lee, Hsiu‐Hsiang; Loppin, Benjamin; Aı̈t-Ahmed, Ounissa; Wu, June‐Tai

doi:10.15252/embr.201439092

Cited by 18 publications

(18 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DGCR8 is a core component of the microprocessor complex involved in processing miRNAs, which regulate gene expression at the protein level by binding target mRNAs to silence their translation (65). HIRA is a histone chaperone that influences gene expression by facilitating the deposition of the non-canonical histone variant, H3.3, into chromatin (66,67).…”

Section: Discussionmentioning

confidence: 99%

Synaptic and Gene Regulatory Mechanisms in Schizophrenia, Autism, and 22q11.2 CNV Mediated Risk for Neuropsychiatric Disorders

Forsyth

Nachun

Gandal

et al. 2019

Preprint

View full text Add to dashboard Cite

Word Count: 244 Main Text Word Count: 4761 Number of Figures: 7 Number of Tables: 2Supplements: 1 supplementary information file + 1 excel file containing 2 supplementary data tables Abstract Background: 22q11.2 copy number variants (CNVs) are among the most highly penetrant genetic risk variants for developmental neuropsychiatric disorders such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the specific mechanisms through which they confer risk remain unclear.Methods: Using a functional genomics approach, we integrated transcriptomic data from the developing human brain, genome-wide association findings for SCZ and ASD, protein interaction data, and pathophysiological signatures of SCZ and ASD to: 1) organize genes into the developmental cellular and molecular systems within which they operate; 2) identify neurodevelopmental processes associated with polygenic risk for SCZ and ASD across the allelic frequency spectrum; and 3) elucidate pathways and individual genes through which 22q11.2 CNVs may confer risk for each disorder.Results: Polygenic risk for SCZ and ASD converged on partially overlapping gene networks involved in synaptic function and transcriptional regulation, with ASD risk variants additionally enriched for networks involved in neuronal differentiation during fetal development. The 22q11.2 locus formed a large protein network that disproportionately affected SCZ-and ASD-associated neurodevelopmental networks, including loading highly onto synaptic and gene regulatory pathways. SEPT5, PI4KA, and SNAP29 genes are candidate drivers of 22q11.2 synaptic pathology relevant to SCZ and ASD, and DGCR8 and HIRA are candidate drivers of disease-relevant alterations in gene regulation. Conclusions:The current approach provides a powerful framework to identify neurodevelopmental processes affected by diverse risk variants for SCZ and ASD and elucidate mechanisms through which highly penetrant multi-gene CNVs contribute to disease risk.(M4,M6,M7,M12,M13,M15). M1 was consistently enriched for ASD risk variants, but not for down-regulated genes in ASD cortex. However, M1 was highly enriched for genes expressed specifically during fetal development, suggesting that this likely reflects a floor effect in postnatal expression of these genes. Down-regulated genes in ASD and SCZ cortextherefore appear to at least partially reflect direct effects of genetic risk, and we focused on 22qBD-PPI network overlap with down-regulated genes for subsequent analyses.Given the size of the 22qBD-PPI network and each DGE gene-set, the 22qBD-PPI network was significantly enriched for down-regulated genes in both SCZ (~11% of the 22qBD-PPI network; p=0.006) and ASD (~14% of the 22qBD-PPI network;p=2.0x10 -4 ). Additionally, compared to all regions of the genome (i.e., Genomic-RegionBD-PPI networks), the 22qBD-PPI network was in the ~93 rd and ~96 th percentiles for overlap with down-regulated genes in SCZ and ASD, respectively ( Fig. 6B; Table S4). Compared to the connectivity of random sets of 38 seed genes (i.e...

show abstract

Section: Discussionmentioning

confidence: 99%

Synaptic and Gene Regulatory Mechanisms in Schizophrenia, Autism, and 22q11.2 CNV Mediated Risk for Neuropsychiatric Disorders

Forsyth

Nachun

Gandal

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Mutant dBRWD3 (also named as ramshackle in Drosophila) leads to dying earlier during the development [8,9] or to disrupt dendritic morphogenesis and sensory organ differentiation [10]. In human, abnormal BRWD3 expression causes intellectual disability [11][12][13][14][15][16][17][18][19], leukemia [20], breast cancer [21] and head & neck cancer [22].…”

Section: Brwd3 (Bromodomain and Wd Repeat Domain Containing 3)mentioning

confidence: 99%

Integrative Networks by BRWD3 Regulates Cytoskeleton Organization and Cell Motility

Li¹,

Wang²,

Cui³

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundEukaryotic cytoskeleton forms and keeps cell shape, transports intracellular particles and organelles, determines cell motility and other important cellular events. A large number of regulators of cytoskeleton organization have been identified, but the detailed regulatory mechanism still remains obscure. Previous reports suggest that BRWD3 may be a regulator of cytoskeleton organization in Drosophila melanogaster, and influences cell shape. Therefore, we investigated the molecular network of BRWD3 regulating cytoskeleton organization.ResultsIn this study, we observed the alteration of cell shape, cell motility, and proliferation when BRWD3 was knocked down in MCF-7 and MDA-MB-231 cell lines. The cells were rounded, cell motility decreased when BRWD3 was knocked down. Using chromatin immunoprecipitation combining with sequencing, we found that BRWD3 influenced the cytoskeleton organization, cell shape, and cell motility through regulating expression of the cytoskeleton associative genes including ARF1, ABI2, ARPC3, ARPC1A, RHOC, MEF2C, and VIM.ConclusionsA molecular network by BRWD3 is sketched to elucidate that BRWD3 may not only regulate actin filament but also regulate microtubule and intermediate filament-based cytoskeleton organization. These efforts provide an overview of a BRWD3 network regulating cytoskeleton organization, cell shape and motility, and allow a better understanding of cytoskeleton (re)organization and pathogenesis of mental retardation X-linked 93 and relative carcinomas.

show abstract

“…However, in addition to confirming the oogenesis defects reported for Bre1 mutants in previous studies, our results uncovered a need for Bre1 in chromosome organization in meiosis or early syncytial divisions. BRWD3 is known to negatively regulate histone H3.3 deposition to the chromatin by interacting with HIRA complex and its associated chaperon Yemanuclein (Yem) in Drosophila (Chen et al 2015). Maternal histone H3.3 is assembled on paternally derived chromosomes shortly after fertilization (Horard & Loppin 2015, Loppin et al 2005.…”

Section: Abnormal Centriolesmentioning

confidence: 99%

Maternal proteins that are phospho-regulated upon egg activation include crucial factors for oogenesis, egg activation and embryogenesis inDrosophila melanogaster

Zhang

Krauchunas

Huang

et al. 2017

Preprint

View full text Add to dashboard Cite

Egg activation is essential for the successful transition from a mature oocyte to a developmentally competent egg. It consists of a series of events including the resumption and completion of meiosis, initiation of translation of some maternal mRNAs and destruction of others, and changes to the vitelline envelope. This drastic change of cell state is accompanied by large scale alteration of the phospho-proteome of the cell. Despite the importance of this transition in cell and developmental state, it has been difficult to find many of its regulators.We hypothesize that phosphorylation state changes between oocyte and early embryo regulate the activities of proteins that are necessary during or after this transition, and thus that the set of phospho-regulated proteins would be an enriched source for finding critical players in the egg-to-embryo transition. To test this, we used germline-specific RNAi to examine the function of 189 maternal proteins that are phospho-regulated during egg activation in Drosophila melanogaster. We identified 53 genes whose knockdown reduced or abolished egg production, as well as 50 genes for which maternal knockdown led to significant impairment or abolishment of the eggs' ability to hatch (hatchability). We observed different stages of developmental arrest in the embryos with impaired hatchability and several distinct categories of abnormalities in the maternal knockdown embryos that arrest early in development, suggesting potential roles of the candidates in egg activation and early embryogenesis. Our results, validated by our detection of multiple genes with previously-documented maternal-effect phenotypes among the proteins we tested, revealed 15 genes with new roles in egg activation and early embryogenesis. Given that protein phospho-regulation also occurs during this All rights reserved. No reuse allowed without permission.

show abstract

Intellectual disability‐associated dBRWD 3 regulates gene expression through inhibition of HIRA / YEM ‐mediated chromatin deposition of histone H3.3

Cited by 18 publications

References 33 publications

Synaptic and Gene Regulatory Mechanisms in Schizophrenia, Autism, and 22q11.2 CNV Mediated Risk for Neuropsychiatric Disorders

Synaptic and Gene Regulatory Mechanisms in Schizophrenia, Autism, and 22q11.2 CNV Mediated Risk for Neuropsychiatric Disorders

Integrative Networks by BRWD3 Regulates Cytoskeleton Organization and Cell Motility

Maternal proteins that are phospho-regulated upon egg activation include crucial factors for oogenesis, egg activation and embryogenesis inDrosophila melanogaster

Contact Info

Product

Resources

About