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  1. Article ; Online: Analysis of epigenetic features characteristic of L1 loci expressed in human cells.

    Freeman, Benjamin / White, Travis / Kaul, Tiffany / Stow, Emily C / Baddoo, Melody / Ungerleider, Nathan / Morales, Maria / Yang, Hanlin / Deharo, Dawn / Deininger, Prescott / Belancio, Victoria P

    Nucleic acids research

    2022  Volume 50, Issue 4, Page(s) 1888–1907

    Abstract: Only a select few L1 loci in the human genome are expressed in any given cell line or organ, likely to minimize damage done to the genome. The epigenetic features and requirements of expressed L1 loci are currently unknown. Using human cells and ... ...

    Abstract Only a select few L1 loci in the human genome are expressed in any given cell line or organ, likely to minimize damage done to the genome. The epigenetic features and requirements of expressed L1 loci are currently unknown. Using human cells and comprehensive epigenetic analysis of individual expressed and unexpressed L1 loci, we determined that endogenous L1 transcription depends on a combination of epigenetic factors, including open chromatin, activating histone modifications, and hypomethylation at the L1 promoter. We demonstrate that the L1 promoter seems to require interaction with enhancer elements for optimal function. We utilize epigenetic context to predict the expression status of L1Hs loci that are poorly mappable with RNA-Seq. Our analysis identified a population of 'transitional' L1 loci that likely have greater potential to be activated during the epigenetic dysregulation seen in tumors and during aging because they are the most responsive to targeted CRISPR-mediated delivery of trans-activating domains. We demonstrate that an engineered increase in endogenous L1 mRNA expression increases Alu mobilization. Overall, our findings present the first global and comprehensive analysis of epigenetic status of individual L1 loci based on their expression status and demonstrate the importance of epigenetic context for L1 expression heterogeneity.
    MeSH term(s) DNA Methylation/genetics ; Epigenesis, Genetic ; Genome, Human ; Humans ; Long Interspersed Nucleotide Elements ; Promoter Regions, Genetic
    Language English
    Publishing date 2022-02-25
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    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/gkac013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1067: Show issues Location:
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  2. Article: Evaluating different DNA binding domains to modulate L1 ORF2p-driven site-specific retrotransposition events in human cells

    Ade, Catherine M / Derbes, Rebecca S / Wagstaff, Bradley J / Linker, Sara B / White, Travis B / Deharo, Dawn / Belancio, Victoria P / Ivics, Zoltán / Roy-Engel, Astrid M

    Gene. 2017,

    2017  

    Abstract: DNA binding domains (DBDs) have been used with great success to impart targeting capabilities to a variety of proteins creating highly useful genomic tools. We evaluated the ability of five types of DBDs and strategies (AAV Rep proteins, Cre, TAL ... ...

    Abstract DNA binding domains (DBDs) have been used with great success to impart targeting capabilities to a variety of proteins creating highly useful genomic tools. We evaluated the ability of five types of DBDs and strategies (AAV Rep proteins, Cre, TAL effectors, zinc finger proteins, and Cas9/gRNA system) to target the L1 ORF2 protein to drive retrotransposition of Alu inserts to specific sequences in the human genome. First, we find that the L1 ORF2 protein tolerates the addition of protein domains both at the amino- and carboxy-terminus. Although in some instances retrotransposition efficiencies slightly diminished, all fusion proteins containing an intact ORF2 were capable of driving retrotransposition. Second, the stability of individual ORF2 fusion proteins varies and difficult to predict. Third, DBDs that require the formation of multimers for target recognition are unlikely to modify targeting of ORF2-driven insertions. Fourth, the more components needed to assemble into a complex to drive targeted retrotransposition, the less likely the strategy will increase targeted insertions. Fifth, abundance of target sequences present in the genome will likely dictate the effectiveness and efficiency of targeted insertions. Lastly, the cleavage capabilities of Cas9 (or a Cas9 nickase variant) are unable to substitute for the L1 ORF2 endonuclease domain functions, suggestive that the endonuclease domain has alternate functions needed for retrotransposition. From these studies, we conclude that the most critical component for the modification of the human L1 ORF2 protein to drive targeted insertions is the selection of the DBD due to the varying functional requirements and impacts on protein stability.
    Keywords genome ; genomics ; humans ; protein domains ; proteins ; zinc finger motif
    Language English
    Publishing place Elsevier B.V.
    Document type Article
    Note Pre-press version
    ZDB-ID 391792-7
    ISSN 1879-0038 ; 0378-1119
    ISSN (online) 1879-0038
    ISSN 0378-1119
    DOI 10.1016/j.gene.2017.11.033
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  3. Article ; Online: Evaluating different DNA binding domains to modulate L1 ORF2p-driven site-specific retrotransposition events in human cells.

    Ade, Catherine M / Derbes, Rebecca S / Wagstaff, Bradley J / Linker, Sara B / White, Travis B / Deharo, Dawn / Belancio, Victoria P / Ivics, Zoltán / Roy-Engel, Astrid M

    Gene

    2017  Volume 642, Page(s) 188–198

    Abstract: DNA binding domains (DBDs) have been used with great success to impart targeting capabilities to a variety of proteins creating highly useful genomic tools. We evaluated the ability of five types of DBDs and strategies (AAV Rep proteins, Cre, TAL ... ...

    Abstract DNA binding domains (DBDs) have been used with great success to impart targeting capabilities to a variety of proteins creating highly useful genomic tools. We evaluated the ability of five types of DBDs and strategies (AAV Rep proteins, Cre, TAL effectors, zinc finger proteins, and Cas9/gRNA system) to target the L1 ORF2 protein to drive retrotransposition of Alu inserts to specific sequences in the human genome. First, we find that the L1 ORF2 protein tolerates the addition of protein domains both at the amino- and carboxy-terminus. Although in some instances retrotransposition efficiencies slightly diminished, all fusion proteins containing an intact ORF2 were capable of driving retrotransposition. Second, the stability of individual ORF2 fusion proteins varies and difficult to predict. Third, DBDs that require the formation of multimers for target recognition are unlikely to modify targeting of ORF2p-driven insertions. Fourth, the more components needed to assemble into a complex to drive targeted retrotransposition, the less likely the strategy will increase targeted insertions. Fifth, abundance of target sequences present in the genome will likely dictate the effectiveness and efficiency of targeted insertions. Lastly, the cleavage capabilities of Cas9 (or a Cas9 nickase variant) are unable to substitute for the L1 ORF2 endonuclease domain functions, suggestive that the endonuclease domain has alternate functions needed for retrotransposition. From these studies, we conclude that the most critical component for the modification of the human L1 ORF2 protein to drive targeted insertions is the selection of the DBD due to the varying functional requirements and impacts on protein stability.
    MeSH term(s) DNA-Binding Proteins/chemistry ; Endonucleases/chemistry ; Endonucleases/genetics ; HeLa Cells ; Humans ; Mutagenesis, Insertional ; Protein Domains ; RNA-Directed DNA Polymerase/chemistry ; RNA-Directed DNA Polymerase/genetics ; Retroelements
    Chemical Substances DNA-Binding Proteins ; L1 ORF2 protein, human ; Retroelements ; RNA-Directed DNA Polymerase (EC 2.7.7.49) ; Endonucleases (EC 3.1.-)
    Language English
    Publishing date 2017-11-14
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 391792-7
    ISSN 1879-0038 ; 0378-1119
    ISSN (online) 1879-0038
    ISSN 0378-1119
    DOI 10.1016/j.gene.2017.11.033
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1357: Show issues Location:
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  4. Article ; Online: C-terminal processing of GABARAP is not required for trafficking of the angiotensin II type 1A receptor.

    Alam, Jawed / Deharo, Dawn / Redding, Kevin M / Re, Richard N / Cook, Julia L

    Regulatory peptides

    2009  Volume 159, Issue 1-3, Page(s) 78–86

    Abstract: Objective: GABARAP, a small (117 aa) trafficking protein, binds to the C-terminal, cytoplasmic domain of rat angiotensin type-1A receptor (AT(1)R), the predominant effector of the octapeptide angiotensin II (Ang II) (Cook et al., Circ. Res. 2008;102: ... ...

    Abstract Objective: GABARAP, a small (117 aa) trafficking protein, binds to the C-terminal, cytoplasmic domain of rat angiotensin type-1A receptor (AT(1)R), the predominant effector of the octapeptide angiotensin II (Ang II) (Cook et al., Circ. Res. 2008;102:1539-47). The objectives of this study were to map the interaction domains of GABARAP and AT(1)R, to determine the effect of GABARAP association on AT(1)R signaling activity, and to determine the importance of post-translational processing of GABARAP on accumulation of AT(1)R on the plasma membrane and its signaling function.
    Results: Deletion analysis identified two regions within GABARAP necessary for interaction with AT(1)R in yeast two-hybrid assays: 1) a domain comprised of residues 32-51 that is nearly identical to that involved in binding and intracellular trafficking of the GABA(A) receptor and 2) a domain encompassing the C-terminal 21 aa. The GABARAP interaction domain of AT(1)R was delimited to the 15 aa immediately downstream of the last membrane spanning region. Overexpression of GABARAP in rat adrenal pheochromocytoma PC-12 cells increased the cell-surface expression of AT(1)R and Ang II-dependent activation of the cAMP signaling pathway. Residues within AT(1)R necessary for these responses were identified by mutational analysis. In PC-12 cells, GABARAP was constitutively and quantitatively cleaved at the C-terminus peptide bond and this cleavage was prevented by mutation of Gly(116). Wild-type GABARAP and the G116A mutant were, however, equally effective in stimulating AT(1)R surface expression and signaling activity.
    Conclusions: GABARAP and AT(1)R interact through discrete domains and this association regulates the cell-surface accumulation and, consequently, ligand-induced function of the receptor. Unlike that observed with the GABA(A) receptor, this regulation is not dependent on C-terminal processing and modification of GABARAP.
    MeSH term(s) Amino Acid Sequence ; Angiotensin II/genetics ; Angiotensin II/metabolism ; Animals ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; PC12 Cells ; Protein Binding/physiology ; Protein Structure, Tertiary/physiology ; Protein Transport/physiology ; Rats ; Receptor, Angiotensin, Type 1/genetics ; Receptor, Angiotensin, Type 1/metabolism ; Sequence Deletion ; Signal Transduction/physiology
    Chemical Substances GABARAP protein, rat ; Microtubule-Associated Proteins ; Receptor, Angiotensin, Type 1 ; Angiotensin II (11128-99-7)
    Language English
    Publishing date 2009-09-17
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 225685-x
    ISSN 1873-1686 ; 0167-0115
    ISSN (online) 1873-1686
    ISSN 0167-0115
    DOI 10.1016/j.regpep.2009.09.002
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    Zs.A 1593: Show issues Location:
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