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  1. Article ; Online: Author Correction: Ybx1 fine-tunes PRC2 activities to control embryonic brain development.

    Evans, Myron K / Matsui, Yurika / Xu, Beisi / Willis, Catherine / Loome, Jennifer / Milburn, Luis / Fan, Yiping / Pagala, Vishwajeeth / Peng, Jamy C

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 412

    Language English
    Publishing date 2023-01-25
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-36069-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Identification of Evolutionarily Conserved VSX2 Enhancers in Retinal Development.

    Honnell, Victoria / Sweeney, Shannon / Norrie, Jackie / Ramirez, Cody / Xu, Beisi / Teubner, Brett / Lee, Ah Young / Bell, Claire / Dyer, Michael A

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Super-enhancers (SEs) are expansive regions of genomic DNA that regulate the expression of genes involved in cell identity and cell fate. Recently, we found that distinct modules within a murine SE regulate gene expression of master regulatory ... ...

    Abstract Super-enhancers (SEs) are expansive regions of genomic DNA that regulate the expression of genes involved in cell identity and cell fate. Recently, we found that distinct modules within a murine SE regulate gene expression of master regulatory transcription factor
    Language English
    Publishing date 2023-10-17
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.17.562742
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Modulation of protease expression by the transcription factor Ptx1/PITX regulates protein quality control during aging.

    Jiao, Jianqin / Curley, Michelle / Graca, Flavia A / Robles-Murguia, Maricela / Shirinifard, Abbas / Finkelstein, David / Xu, Beisi / Fan, Yiping / Demontis, Fabio

    Cell reports

    2023  Volume 42, Issue 1, Page(s) 111970

    Abstract: Protein quality control is important for healthy aging and is dysregulated in age-related diseases. The autophagy-lysosome and ubiquitin-proteasome are key for proteostasis, but it remains largely unknown whether other proteolytic systems also contribute ...

    Abstract Protein quality control is important for healthy aging and is dysregulated in age-related diseases. The autophagy-lysosome and ubiquitin-proteasome are key for proteostasis, but it remains largely unknown whether other proteolytic systems also contribute to maintain proteostasis during aging. Here, we find that expression of proteolytic enzymes (proteases/peptidases) distinct from the autophagy-lysosome and ubiquitin-proteasome systems declines during skeletal muscle aging in Drosophila. Age-dependent protease downregulation undermines proteostasis, as demonstrated by the increase in detergent-insoluble poly-ubiquitinated proteins and pathogenic huntingtin-polyQ levels in response to protease knockdown. Computational analyses identify the transcription factor Ptx1 (homologous to human PITX1/2/3) as a regulator of protease expression. Consistent with this model, Ptx1 protein levels increase with aging, and Ptx1 RNAi counteracts the age-associated downregulation of protease expression. Moreover, Ptx1 RNAi improves muscle protein quality control in a protease-dependent manner and extends lifespan. These findings indicate that proteases and their transcriptional modulator Ptx1 ensure proteostasis during aging.
    MeSH term(s) Humans ; Aging/metabolism ; Endopeptidases/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis ; Transcription Factors/metabolism ; Ubiquitins/metabolism ; Animals ; Drosophila
    Chemical Substances Endopeptidases (EC 3.4.-) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Transcription Factors ; Ubiquitins ; Ptx1 protein, Drosophila
    Language English
    Publishing date 2023-01-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2022.111970
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Latent Epigenetic Programs in Müller Glia Contribute to Stress, Injury, and Disease Response in the Retina.

    Norrie, Jackie L / Lupo, Marybeth / Shirinifard, Abbas / Djekidel, Nadhir / Ramirez, Cody / Xu, Beisi / Dundee, Jacob M / Dyer, Michael A

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Previous studies have demonstrated the dynamic changes in chromatin structure during retinal development that correlate with changes in gene expression. However, a major limitation of those prior studies was the lack of cellular resolution. Here, we ... ...

    Abstract Previous studies have demonstrated the dynamic changes in chromatin structure during retinal development that correlate with changes in gene expression. However, a major limitation of those prior studies was the lack of cellular resolution. Here, we integrate single-cell (sc) RNA-seq and scATAC-seq with bulk retinal data sets to identify cell type-specific changes in the chromatin structure during development. Although most genes' promoter activity is strongly correlated with chromatin accessibility, we discovered several hundred genes that were transcriptionally silent but had accessible chromatin at their promoters. Most of those silent/accessible gene promoters were in the Müller glial cells. The Müller cells are radial glia of the retina and perform a variety of essential functions to maintain retinal homeostasis and respond to stress, injury, or disease. The silent/accessible genes in Müller glia are enriched in pathways related to inflammation, angiogenesis, and other types of cell-cell signaling and were rapidly activated when we tested 15 different physiologically relevant conditions to mimic retinal stress, injury, or disease in human and murine retinae. We refer to these as "pliancy genes" because they allow the Müller glia to rapidly change their gene expression and cellular state in response to different types of retinal insults. The Müller glial cell pliancy program is established during development, and we demonstrate that pliancy genes are necessary and sufficient for regulating inflammation in the murine retina in vivo. In zebrafish, Müller glia can de-differentiate and form retinal progenitor cells that replace lost neurons. The pro-inflammatory pliancy gene cascade is not activated in zebrafish Müller glia following injury, and we propose a model in which species-specific pliancy programs underly the differential response to retinal damage in species that can regenerate retinal neurons (zebrafish) versus those that cannot (humans and mice).
    Language English
    Publishing date 2023-10-17
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.15.562396
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Auxin-inducible degron 2 system deciphers functions of CTCF domains in transcriptional regulation.

    Hyle, Judith / Djekidel, Mohamed Nadhir / Williams, Justin / Wright, Shaela / Shao, Ying / Xu, Beisi / Li, Chunliang

    Genome biology

    2023  Volume 24, Issue 1, Page(s) 14

    Abstract: Background: CTCF is a well-established chromatin architectural protein that also plays various roles in transcriptional regulation. While CTCF biology has been extensively studied, how the domains of CTCF function to regulate transcription remains ... ...

    Abstract Background: CTCF is a well-established chromatin architectural protein that also plays various roles in transcriptional regulation. While CTCF biology has been extensively studied, how the domains of CTCF function to regulate transcription remains unknown. Additionally, the original auxin-inducible degron 1 (AID1) system has limitations in investigating the function of CTCF.
    Results: We employ an improved auxin-inducible degron technology, AID2, to facilitate the study of acute depletion of CTCF while overcoming the limitations of the previous AID system. As previously observed through the AID1 system and steady-state RNA analysis, the new AID2 system combined with SLAM-seq confirms that CTCF depletion leads to modest nascent and steady-state transcript changes. A CTCF domain sgRNA library screening identifies the zinc finger (ZF) domain as the region within CTCF with the most functional relevance, including ZFs 1 and 10. Removal of ZFs 1 and 10 reveals genomic regions that independently require these ZFs for DNA binding and transcriptional regulation. Notably, loci regulated by either ZF1 or ZF10 exhibit unique CTCF binding motifs specific to each ZF.
    Conclusions: By extensively comparing the AID1 and AID2 systems for CTCF degradation in SEM cells, we confirm that AID2 degradation is superior for achieving miniAID-tagged protein degradation without the limitations of the AID1 system. The model we create that combines AID2 depletion of CTCF with exogenous overexpression of CTCF mutants allows us to demonstrate how peripheral ZFs intricately orchestrate transcriptional regulation in a cellular context for the first time.
    MeSH term(s) CCCTC-Binding Factor/metabolism ; Indoleacetic Acids ; Gene Expression Regulation ; Zinc Fingers ; Genome
    Chemical Substances CCCTC-Binding Factor ; Indoleacetic Acids
    Language English
    Publishing date 2023-01-26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2040529-7
    ISSN 1474-760X ; 1474-760X
    ISSN (online) 1474-760X
    ISSN 1474-760X
    DOI 10.1186/s13059-022-02843-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: A Novel Single Vector Intersectional AAV Strategy for Interrogating Cellular Diversity and Brain Function.

    Hughes, Alex C / Pollard, Brittany G / Xu, Beisi / Gammons, Jesse W / Chapman, Phillip / Bikoff, Jay B / Schwarz, Lindsay A

    bioRxiv : the preprint server for biology

    2023  

    Abstract: As the discovery of cellular diversity in the brain accelerates, so does the need for functional tools that target cells based on multiple features, such as gene expression and projection target. By selectively driving recombinase expression in a feature- ...

    Abstract As the discovery of cellular diversity in the brain accelerates, so does the need for functional tools that target cells based on multiple features, such as gene expression and projection target. By selectively driving recombinase expression in a feature-specific manner, one can utilize intersectional strategies to conditionally promote payload expression only where multiple features overlap. We developed Conditional Viral Expression by Ribozyme Guided Degradation (ConVERGD), a single-construct intersectional targeting strategy that combines a self-cleaving ribozyme with traditional FLEx switches. ConVERGD offers benefits over existing platforms, such as expanded intersectionality, the ability to accommodate larger and more complex payloads, and a vector design that is easily modified to better facilitate rapid toolkit expansion. To demonstrate its utility for interrogating neural circuitry, we employed ConVERGD to target an unexplored subpopulation of norepinephrine (NE)-producing neurons within the rodent locus coeruleus (LC) identified via single-cell transcriptomic profiling to co-express the stress-related endogenous opioid gene prodynorphin (
    Language English
    Publishing date 2023-02-08
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.02.07.527312
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: THUMPD2 catalyzes the N2-methylation of U6 snRNA of the spliceosome catalytic center and regulates pre-mRNA splicing and retinal degeneration.

    Yang, Wen-Qing / Ge, Jian-Yang / Zhang, Xiaofeng / Zhu, Wen-Yu / Lin, Lin / Shi, Yigong / Xu, Beisi / Liu, Ru-Juan

    Nucleic acids research

    2023  Volume 52, Issue 6, Page(s) 3291–3309

    Abstract: The mechanisms by which the relatively conserved spliceosome manages the enormously large number of splicing events that occur in humans (∼200 000 versus ∼300 in yeast) are poorly understood. Here, we show deposition of one RNA modification-N2- ... ...

    Abstract The mechanisms by which the relatively conserved spliceosome manages the enormously large number of splicing events that occur in humans (∼200 000 versus ∼300 in yeast) are poorly understood. Here, we show deposition of one RNA modification-N2-methylguanosine (m2G) on the G72 of U6 snRNA (the catalytic center of the spliceosome) promotes efficient pre-mRNA splicing activity in human cells. This modification was identified to be conserved among vertebrates. Further, THUMPD2 was demonstrated as the methyltransferase responsible for U6 m2G72 by explicitly recognizing the U6-specific sequences and structural elements. The knock-out of THUMPD2 eliminated U6 m2G72 and impaired the pre-mRNA splicing activity, resulting in thousands of changed alternative splicing events of endogenous pre-mRNAs in human cells. Notably, the aberrantly spliced pre-mRNA population elicited the nonsense-mediated mRNA decay pathway. We further show that THUMPD2 was associated with age-related macular degeneration and retinal function. Our study thus demonstrates how an RNA epigenetic modification of the major spliceosome regulates global pre-mRNA splicing and impacts physiology and disease.
    MeSH term(s) Animals ; Humans ; RNA Precursors/genetics ; RNA Precursors/metabolism ; Spliceosomes/genetics ; Spliceosomes/metabolism ; Retinal Degeneration/metabolism ; RNA Splicing/genetics ; RNA, Small Nuclear/metabolism ; Methylation ; Saccharomyces cerevisiae/genetics ; Nucleic Acid Conformation
    Chemical Substances RNA Precursors ; U6 small nuclear RNA ; RNA, Small Nuclear
    Language English
    Publishing date 2023-12-29
    Publishing country England
    Document type Journal Article
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkad1243
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: MethylationToActivity: a deep-learning framework that reveals promoter activity landscapes from DNA methylomes in individual tumors

    Williams, Justin / Xu, Beisi / Putnam, Daniel / Thrasher, Andrew / Li, Chunliang / Yang, Jun / Chen, Xiang

    Genome biology. 2021 Dec., v. 22, no. 1

    2021  

    Abstract: Although genome-wide DNA methylomes have demonstrated their clinical value as reliable biomarkers for tumor detection, subtyping, and classification, their direct biological impacts at the individual gene level remain elusive. Here we present ... ...

    Abstract Although genome-wide DNA methylomes have demonstrated their clinical value as reliable biomarkers for tumor detection, subtyping, and classification, their direct biological impacts at the individual gene level remain elusive. Here we present MethylationToActivity (M2A), a machine learning framework that uses convolutional neural networks to infer promoter activities based on H3K4me3 and H3K27ac enrichment, from DNA methylation patterns for individual genes. Using publicly available datasets in real-world test scenarios, we demonstrate that M2A is highly accurate and robust in revealing promoter activity landscapes in various pediatric and adult cancers, including both solid and hematologic malignant neoplasms.
    Keywords DNA ; DNA methylation ; adults ; artificial intelligence ; biomarkers ; classification ; data collection ; detection ; genes ; landscapes ; neoplasms ; neural networks
    Language English
    Dates of publication 2021-12
    Size p. 24.
    Publishing place BioMed Central
    Document type Article
    ZDB-ID 2040529-7
    ISSN 1474-760X
    ISSN 1474-760X
    DOI 10.1186/s13059-020-02220-y
    Database NAL-Catalogue (AGRICOLA)

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  9. Article ; Online: MethylationToActivity: a deep-learning framework that reveals promoter activity landscapes from DNA methylomes in individual tumors.

    Williams, Justin / Xu, Beisi / Putnam, Daniel / Thrasher, Andrew / Li, Chunliang / Yang, Jun / Chen, Xiang

    Genome biology

    2021  Volume 22, Issue 1, Page(s) 24

    Abstract: Although genome-wide DNA methylomes have demonstrated their clinical value as reliable biomarkers for tumor detection, subtyping, and classification, their direct biological impacts at the individual gene level remain elusive. Here we present ... ...

    Abstract Although genome-wide DNA methylomes have demonstrated their clinical value as reliable biomarkers for tumor detection, subtyping, and classification, their direct biological impacts at the individual gene level remain elusive. Here we present MethylationToActivity (M2A), a machine learning framework that uses convolutional neural networks to infer promoter activities based on H3K4me3 and H3K27ac enrichment, from DNA methylation patterns for individual genes. Using publicly available datasets in real-world test scenarios, we demonstrate that M2A is highly accurate and robust in revealing promoter activity landscapes in various pediatric and adult cancers, including both solid and hematologic malignant neoplasms.
    MeSH term(s) Cell Line, Tumor ; DNA Methylation ; Deep Learning ; Gene Expression Regulation, Neoplastic ; Histones/genetics ; Histones/metabolism ; Humans ; Machine Learning ; Neoplasms/genetics ; Neural Networks, Computer ; Promoter Regions, Genetic ; Sarcoma
    Chemical Substances Histones ; histone H3 trimethyl Lys4
    Language English
    Publishing date 2021-01-19
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2040529-7
    ISSN 1474-760X ; 1474-760X
    ISSN (online) 1474-760X
    ISSN 1474-760X
    DOI 10.1186/s13059-020-02220-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Genomic profiling identifies genes and pathways dysregulated by HEY1-NCOA2 fusion and shines a light on mesenchymal chondrosarcoma tumorigenesis.

    Qi, Wenqing / Rosikiewicz, Wojciech / Yin, Zhaohong / Xu, Beisi / Jiang, Huihong / Wan, Shibiao / Fan, Yiping / Wu, Gang / Wang, Lu

    The Journal of pathology

    2022  Volume 257, Issue 5, Page(s) 579–592

    Abstract: Mesenchymal chondrosarcoma is a rare, high-grade, primitive mesenchymal tumor. It accounts for around 2-10% of all chondrosarcomas and mainly affects adolescents and young adults. We previously described the HEY1-NCOA2 as a recurrent gene fusion in ... ...

    Abstract Mesenchymal chondrosarcoma is a rare, high-grade, primitive mesenchymal tumor. It accounts for around 2-10% of all chondrosarcomas and mainly affects adolescents and young adults. We previously described the HEY1-NCOA2 as a recurrent gene fusion in mesenchymal chondrosarcoma, an important breakthrough for characterizing this disease; however, little study had been done to characterize the fusion protein functionally, in large part due to a lack of suitable models for evaluating the impact of HEY1-NCOA2 expression in the appropriate cellular context. We used iPSC-derived mesenchymal stem cells (iPSC-MSCs), which can differentiate into chondrocytes, and generated stable transduced iPSC-MSCs with inducible expression of HEY1-NCOA2 fusion protein, wildtype HEY1 or wildtype NCOA2. We next comprehensively analyzed both the DNA binding properties and transcriptional impact of HEY1-NCOA2 expression by integrating genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) and expression profiling (RNA-seq). We demonstrated that HEY1-NCOA2 fusion protein preferentially binds to promoter regions of canonical HEY1 targets, resulting in transactivation of HEY1 targets, and significantly enhances cell proliferation. Intriguingly, we identified that both PDGFB and PDGFRA were directly targeted and upregulated by HEY1-NCOA2; and the fusion protein, but not wildtype HEY1 or NCOA2, dramatically increased the level of phospho-AKT (Ser473). Our findings provide a rationale for exploring PDGF/PI3K/AKT inhibition in treating mesenchymal chondrosarcoma. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
    MeSH term(s) Adolescent ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Bone Neoplasms/genetics ; Bone Neoplasms/pathology ; Carcinogenesis ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Transformation, Neoplastic ; Chondrosarcoma, Mesenchymal/genetics ; Chondrosarcoma, Mesenchymal/metabolism ; Chondrosarcoma, Mesenchymal/pathology ; Gene Fusion ; Genomics ; Humans ; Nuclear Receptor Coactivator 2/genetics ; Nuclear Receptor Coactivator 2/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Young Adult
    Chemical Substances Basic Helix-Loop-Helix Transcription Factors ; Cell Cycle Proteins ; HEY1 protein, human ; NCOA2 protein, human ; Nuclear Receptor Coactivator 2 ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
    Language English
    Publishing date 2022-04-26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3119-7
    ISSN 1096-9896 ; 0022-3417
    ISSN (online) 1096-9896
    ISSN 0022-3417
    DOI 10.1002/path.5899
    Database MEDical Literature Analysis and Retrieval System OnLINE

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