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  1. Article ; Online: BRD9 Is a Critical Regulator of Androgen Receptor Signaling and Prostate Cancer Progression.

    Alpsoy, Aktan / Utturkar, Sagar M / Carter, Benjamin C / Dhiman, Alisha / Torregrosa-Allen, Sandra E / Currie, Melanie P / Elzey, Bennett D / Dykhuizen, Emily C

    Cancer research

    2020  Volume 81, Issue 4, Page(s) 820–833

    Abstract: Switch/sucrose-nonfermentable (SWI/SNF) chromatin-remodeling complexes are critical regulators of chromatin dynamics during transcription, DNA replication, and DNA repair. A recently identified SWI/SNF subcomplex termed GLTSCR1/1L-BAF (GBAF; or " ... ...

    Abstract Switch/sucrose-nonfermentable (SWI/SNF) chromatin-remodeling complexes are critical regulators of chromatin dynamics during transcription, DNA replication, and DNA repair. A recently identified SWI/SNF subcomplex termed GLTSCR1/1L-BAF (GBAF; or "noncanonical BAF", ncBAF) uniquely contains bromodomain-containing protein BRD9 and glioma tumor suppressor candidate region 1 (GLTSCR1) or its paralog GLTSCR1-like (GLTSCR1L). Recent studies have identified a unique dependency on GBAF (ncBAF) complexes in synovial sarcoma and malignant rhabdoid tumors, both of which possess aberrations in canonical BAF (cBAF) and Polybromo-BAF (PBAF) complexes. Dependencies on GBAF in malignancies without SWI/SNF aberrations, however, are less defined. Here, we show that GBAF, particularly its BRD9 subunit, is required for the viability of prostate cancer cell lines
    MeSH term(s) Androgen Receptor Antagonists/pharmacology ; Animals ; Cell Line, Tumor ; Cell Proliferation/genetics ; Cell Survival/drug effects ; Cell Survival/genetics ; Disease Progression ; Gene Expression Regulation, Neoplastic/drug effects ; HEK293 Cells ; Humans ; Male ; Mice ; Mice, Nude ; PC-3 Cells ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; RNA, Small Interfering/pharmacology ; Receptors, Androgen/genetics ; Receptors, Androgen/metabolism ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/genetics ; Transcription Factors/physiology ; Xenograft Model Antitumor Assays
    Chemical Substances AR protein, human ; Androgen Receptor Antagonists ; BRD9 protein, human ; RNA, Small Interfering ; Receptors, Androgen ; Transcription Factors
    Language English
    Publishing date 2020-12-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-20-1417
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Perturbation of H3K27me3-Associated Epigenetic Processes Increases Agrobacterium-Mediated Transformation

    Iwakawa, Hidekazu / Bishop Brett C / Carter Benjamin C / Gelvin Stanton B / Ogas Joe

    Molecular plant-microbe interactions. 2017 Jan., v. 30, no. 1

    2017  

    Abstract: Agrobacterium-mediated transformation is a core technology for basic plant science and agricultural biotechnology. Improving transformation frequency is a major goal for plant transgenesis. We previously showed that T-DNA insertions in some histone genes ...

    Abstract Agrobacterium-mediated transformation is a core technology for basic plant science and agricultural biotechnology. Improving transformation frequency is a major goal for plant transgenesis. We previously showed that T-DNA insertions in some histone genes decreased transformation susceptibility, whereas overexpression of several Arabidopsis H2A and H4 isoforms increased transformation. Overexpression of several histone H2B and H3 isoforms had little effect on transformation frequency. However, overexpression of histone H3-11 (HTR11) enhanced transformation. HTR11 is a unique H3 variant that lacks lysine at positions 9 and 27. The modification status of these lysine residues in canonical H3 proteins plays a critical role in epigenetic determination of gene expression. We mutated histone H3-4 (HTR4), a canonical H3.3 protein that does not increase transformation when overexpressed, by replacing either or both K9 and K27 with the amino acids in HTR11 (either K9I, K27Q, or both). Overexpression of HTR4 with the K27Q but not the K9I substitution enhanced transformation. HTR4ᴷ²⁷Q was incorporated into chromatin, and HTR4ᴷ²⁷Q overexpression lines exhibited deregulated expression of H3K27me3-enriched genes. These results demonstrate that mutation of K27 in H3.3 is sufficient to perturb H3K27me3-dependent expression in plants as in animals and suggest a distinct epigenetic role for histone HTR11. Further, these observations implicate manipulation of H3K27me3-dependent gene expression as a novel strategy to increase transformation susceptibility.
    Keywords agricultural biotechnology ; animals ; Arabidopsis ; chromatin ; epigenetics ; gene overexpression ; genes ; histones ; lysine ; mutation ; transfer DNA ; transgenesis
    Language English
    Dates of publication 2017-01
    Size p. 35-44.
    Publishing place Molecular Plant-Microbe Interactions
    Document type Article
    ZDB-ID 743331-1
    ISSN 1943-7706 ; 0894-0282
    ISSN (online) 1943-7706
    ISSN 0894-0282
    DOI 10.1094%2FMPMI-12-16-0250-R
    Database NAL-Catalogue (AGRICOLA)

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  3. Article: Overexpression of arogenate dehydratase reveals an upstream point of metabolic control in phenylalanine biosynthesis

    Yoo, Heejin / Shrivastava, Stuti / Lynch, Joseph H. / Huang, Xing‐Qi / Widhalm, Joshua R. / Guo, Longyun / Carter, Benjamin C. / Qian, Yichun / Maeda, Hiroshi A. / Ogas, Joseph P. / Morgan, John A. / Marshall‐Colón, Amy / Dudareva, Natalia

    plant journal. 2021 Nov., v. 108, no. 3

    2021  

    Abstract: Out of the three aromatic amino acids, the highest flux in plants is directed towards phenylalanine, which is utilized to synthesize proteins and thousands of phenolic metabolites contributing to plant fitness. Phenylalanine is produced predominantly in ... ...

    Abstract Out of the three aromatic amino acids, the highest flux in plants is directed towards phenylalanine, which is utilized to synthesize proteins and thousands of phenolic metabolites contributing to plant fitness. Phenylalanine is produced predominantly in plastids via the shikimate pathway and subsequent arogenate pathway, both of which are subject to complex transcriptional and post‐transcriptional regulation. Previously, it was shown that allosteric feedback inhibition of arogenate dehydratase (ADT), which catalyzes the final step of the arogenate pathway, restricts flux through phenylalanine biosynthesis. Here, we show that in petunia (Petunia hybrida) flowers, which typically produce high phenylalanine levels, ADT regulation is relaxed, but not eliminated. Moderate expression of a feedback‐insensitive ADT increased flux towards phenylalanine, while high overexpression paradoxically reduced phenylalanine formation. This reduction could be partially, but not fully, recovered by bypassing other known metabolic flux control points in the aromatic amino acid network. Using comparative transcriptomics, reverse genetics, and metabolic flux analysis, we discovered that transcriptional regulation of the d‐ribulose‐5‐phosphate 3‐epimerase gene in the pentose phosphate pathway controls flux into the shikimate pathway. Taken together, our findings reveal that regulation within and upstream of the shikimate pathway shares control over phenylalanine biosynthesis in the plant cell.
    Keywords Petunia hybrida ; biosynthesis ; genes ; metabolic flux analysis ; metabolites ; pentose phosphate cycle ; phenylalanine ; plastids ; reverse genetics ; shikimate pathway ; transcription (genetics) ; transcriptomics
    Language English
    Dates of publication 2021-11
    Size p. 737-751.
    Publishing place John Wiley & Sons, Ltd
    Document type Article
    Note JOURNAL ARTICLE
    ZDB-ID 1088037-9
    ISSN 1365-313X ; 0960-7412
    ISSN (online) 1365-313X
    ISSN 0960-7412
    DOI 10.1111/tpj.15467
    Database NAL-Catalogue (AGRICOLA)

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  4. Article: Perturbation of H3K27me3-Associated Epigenetic Processes Increases Agrobacterium-Mediated Transformation.

    Iwakawa, Hidekazu / Carter, Benjamin C / Bishop, Brett C / Ogas, Joe / Gelvin, Stanton B

    Molecular plant-microbe interactions : MPMI

    2017  Volume 30, Issue 1, Page(s) 35–44

    Abstract: Agrobacterium-mediated transformation is a core technology for basic plant science and agricultural biotechnology. Improving transformation frequency is a major goal for plant transgenesis. We previously showed that T-DNA insertions in some histone genes ...

    Abstract Agrobacterium-mediated transformation is a core technology for basic plant science and agricultural biotechnology. Improving transformation frequency is a major goal for plant transgenesis. We previously showed that T-DNA insertions in some histone genes decreased transformation susceptibility, whereas overexpression of several Arabidopsis H2A and H4 isoforms increased transformation. Overexpression of several histone H2B and H3 isoforms had little effect on transformation frequency. However, overexpression of histone H3-11 (HTR11) enhanced transformation. HTR11 is a unique H3 variant that lacks lysine at positions 9 and 27. The modification status of these lysine residues in canonical H3 proteins plays a critical role in epigenetic determination of gene expression. We mutated histone H3-4 (HTR4), a canonical H3.3 protein that does not increase transformation when overexpressed, by replacing either or both K9 and K27 with the amino acids in HTR11 (either K9I, K27Q, or both). Overexpression of HTR4 with the K27Q but not the K9I substitution enhanced transformation. HTR4
    Language English
    Publishing date 2017-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 743331-1
    ISSN 1943-7706 ; 0894-0282
    ISSN (online) 1943-7706
    ISSN 0894-0282
    DOI 10.1094/MPMI-12-16-0250-R
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Overexpression of arogenate dehydratase reveals an upstream point of metabolic control in phenylalanine biosynthesis.

    Yoo, Heejin / Shrivastava, Stuti / Lynch, Joseph H / Huang, Xing-Qi / Widhalm, Joshua R / Guo, Longyun / Carter, Benjamin C / Qian, Yichun / Maeda, Hiroshi A / Ogas, Joseph P / Morgan, John A / Marshall-Colón, Amy / Dudareva, Natalia

    The Plant journal : for cell and molecular biology

    2021  Volume 108, Issue 3, Page(s) 737–751

    Abstract: Out of the three aromatic amino acids, the highest flux in plants is directed towards phenylalanine, which is utilized to synthesize proteins and thousands of phenolic metabolites contributing to plant fitness. Phenylalanine is produced predominantly in ... ...

    Abstract Out of the three aromatic amino acids, the highest flux in plants is directed towards phenylalanine, which is utilized to synthesize proteins and thousands of phenolic metabolites contributing to plant fitness. Phenylalanine is produced predominantly in plastids via the shikimate pathway and subsequent arogenate pathway, both of which are subject to complex transcriptional and post-transcriptional regulation. Previously, it was shown that allosteric feedback inhibition of arogenate dehydratase (ADT), which catalyzes the final step of the arogenate pathway, restricts flux through phenylalanine biosynthesis. Here, we show that in petunia (Petunia hybrida) flowers, which typically produce high phenylalanine levels, ADT regulation is relaxed, but not eliminated. Moderate expression of a feedback-insensitive ADT increased flux towards phenylalanine, while high overexpression paradoxically reduced phenylalanine formation. This reduction could be partially, but not fully, recovered by bypassing other known metabolic flux control points in the aromatic amino acid network. Using comparative transcriptomics, reverse genetics, and metabolic flux analysis, we discovered that transcriptional regulation of the d-ribulose-5-phosphate 3-epimerase gene in the pentose phosphate pathway controls flux into the shikimate pathway. Taken together, our findings reveal that regulation within and upstream of the shikimate pathway shares control over phenylalanine biosynthesis in the plant cell.
    MeSH term(s) Carbohydrate Epimerases/genetics ; Carbohydrate Epimerases/metabolism ; Flowers/genetics ; Flowers/metabolism ; Gene Expression Regulation, Plant ; Hydro-Lyases/genetics ; Hydro-Lyases/metabolism ; Mutation ; Petunia/genetics ; Petunia/metabolism ; Phenylalanine/biosynthesis ; Phenylalanine/metabolism ; Plant Proteins/genetics ; Plant Proteins/metabolism ; Plants, Genetically Modified ; Plastids/genetics ; Plastids/metabolism ; Secondary Metabolism/genetics ; Shikimic Acid/metabolism
    Chemical Substances Plant Proteins ; Shikimic Acid (29MS2WI2NU) ; Phenylalanine (47E5O17Y3R) ; Hydro-Lyases (EC 4.2.1.-) ; pretyrosine dehydratase (EC 4.2.1.-) ; Carbohydrate Epimerases (EC 5.1.3.-) ; ribulosephosphate 3-epimerase (EC 5.1.3.1)
    Language English
    Publishing date 2021-09-09
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1088037-9
    ISSN 1365-313X ; 0960-7412
    ISSN (online) 1365-313X
    ISSN 0960-7412
    DOI 10.1111/tpj.15467
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: PBRM1 Regulates Stress Response in Epithelial Cells.

    Porter, Elizabeth G / Dhiman, Alisha / Chowdhury, Basudev / Carter, Benjamin C / Lin, Hang / Stewart, Jane C / Kazemian, Majid / Wendt, Michael K / Dykhuizen, Emily C

    iScience

    2019  Volume 15, Page(s) 196–210

    Abstract: Polybromo1 (PBRM1) is a chromatin remodeler subunit highly mutated in cancer, particularly clear cell renal carcinoma. PBRM1 is a member of the SWI/SNF subcomplex, PBAF (PBRM1-Brg1/Brm-associated factors), and is characterized by six tandem bromodomains. ...

    Abstract Polybromo1 (PBRM1) is a chromatin remodeler subunit highly mutated in cancer, particularly clear cell renal carcinoma. PBRM1 is a member of the SWI/SNF subcomplex, PBAF (PBRM1-Brg1/Brm-associated factors), and is characterized by six tandem bromodomains. Here we establish a role for PBRM1 in epithelial cell maintenance through the expression of genes involved in cell adhesion, metabolism, stress response, and apoptosis. In support of a general role for PBRM1 in stress response and apoptosis, we observe that loss of PBRM1 results in an increase in reactive oxygen species generation and a decrease in cellular viability under stress conditions. We find that loss of PBRM1 promotes cell growth under favorable conditions but is required for cell survival under conditions of cellular stress.
    Language English
    Publishing date 2019-04-26
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2019.04.027
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Small Molecule Targeting of Specific BAF (mSWI/SNF) Complexes for HIV Latency Reversal.

    Marian, Christine A / Stoszko, Mateusz / Wang, Lili / Leighty, Matthew W / de Crignis, Elisa / Maschinot, Chad A / Gatchalian, Jovylyn / Carter, Benjamin C / Chowdhury, Basudev / Hargreaves, Diana C / Duvall, Jeremy R / Crabtree, Gerald R / Mahmoudi, Tokameh / Dykhuizen, Emily C

    Cell chemical biology

    2018  Volume 25, Issue 12, Page(s) 1443–1455.e14

    Abstract: The persistence of a pool of latently HIV-1-infected cells despite combination anti-retroviral therapy treatment is the major roadblock for a cure. The BAF (mammalian SWI/SNF) chromatin remodeling complex is involved in establishing and maintaining viral ...

    Abstract The persistence of a pool of latently HIV-1-infected cells despite combination anti-retroviral therapy treatment is the major roadblock for a cure. The BAF (mammalian SWI/SNF) chromatin remodeling complex is involved in establishing and maintaining viral latency, making it an attractive drug target for HIV-1 latency reversal. Here we report a high-throughput screen for inhibitors of BAF-mediated transcription in cells and the subsequent identification of a 12-membered macrolactam. This compound binds ARID1A-specific BAF complexes, prevents nucleosomal positioning, and relieves transcriptional repression of HIV-1. Through this mechanism, these compounds are able to reverse HIV-1 latency in an in vitro T cell line, an ex vivo primary cell model of HIV-1 latency, and in patient CD4+ T cells without toxicity or T cell activation. These macrolactams represent a class of latency reversal agents with unique mechanism of action, and can be combined with other latency reversal agents to improve reservoir targeting.
    MeSH term(s) Animals ; Cell Line ; Chromosomal Proteins, Non-Histone/antagonists & inhibitors ; Chromosomal Proteins, Non-Histone/metabolism ; HIV-1/drug effects ; HIV-1/growth & development ; High-Throughput Screening Assays ; Mice ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/metabolism ; Transcription, Genetic/drug effects ; Virus Latency/drug effects ; Virus Latency/genetics
    Chemical Substances Chromosomal Proteins, Non-Histone ; SWI-SNF-B chromatin-remodeling complex ; Small Molecule Libraries ; Transcription Factors
    Language English
    Publishing date 2018-09-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 2451-9448
    ISSN (online) 2451-9448
    DOI 10.1016/j.chembiol.2018.08.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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