Forced enhancer-promoter rewiring to alter gene expression in animal models
Transcriptional enhancers can be in physical proximity of their target genes via chromatin looping. The enhancer at the β-globin locus (locus control region [LCR]) contacts the fetal-type (HBG) and adult-type (HBB) β-globin genes during corresponding developmental stages. We have demonstrated previo...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253123000197 |
| _version_ | 1797905311921602560 |
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| author | Scott A. Peslak Selami Demirci Vemika Chandra Byoung Ryu Saurabh K. Bhardwaj Jing Jiang Jeremy W. Rupon Robert E. Throm Naoya Uchida Alexis Leonard Khaled Essawi Aylin C. Bonifacino Allen E. Krouse Nathaniel S. Linde Robert E. Donahue Francesca Ferrara Matthew Wielgosz Osheiza Abdulmalik Nicole Hamagami Paula Germino-Watnick Anh Le Rebecca Chu Malikiya Hinds Mitchell J. Weiss Wei Tong John F. Tisdale Gerd A. Blobel |
| author_facet | Scott A. Peslak Selami Demirci Vemika Chandra Byoung Ryu Saurabh K. Bhardwaj Jing Jiang Jeremy W. Rupon Robert E. Throm Naoya Uchida Alexis Leonard Khaled Essawi Aylin C. Bonifacino Allen E. Krouse Nathaniel S. Linde Robert E. Donahue Francesca Ferrara Matthew Wielgosz Osheiza Abdulmalik Nicole Hamagami Paula Germino-Watnick Anh Le Rebecca Chu Malikiya Hinds Mitchell J. Weiss Wei Tong John F. Tisdale Gerd A. Blobel |
| author_sort | Scott A. Peslak |
| collection | DOAJ |
| description | Transcriptional enhancers can be in physical proximity of their target genes via chromatin looping. The enhancer at the β-globin locus (locus control region [LCR]) contacts the fetal-type (HBG) and adult-type (HBB) β-globin genes during corresponding developmental stages. We have demonstrated previously that forcing proximity between the LCR and HBG genes in cultured adult-stage erythroid cells can activate HBG transcription. Activation of HBG expression in erythroid cells is of benefit to patients with sickle cell disease. Here, using the β-globin locus as a model, we provide proof of concept at the organismal level that forced enhancer rewiring might present a strategy to alter gene expression for therapeutic purposes. Hematopoietic stem and progenitor cells (HSPCs) from mice bearing human β-globin genes were transduced with lentiviral vectors expressing a synthetic transcription factor (ZF-Ldb1) that fosters LCR-HBG contacts. When engrafted into host animals, HSPCs gave rise to adult-type erythroid cells with elevated HBG expression. Vectors containing ZF-Ldb1 were optimized for activity in cultured human and rhesus macaque erythroid cells. Upon transplantation into rhesus macaques, erythroid cells from HSPCs expressing ZF-Ldb1 displayed elevated HBG production. These findings in two animal models suggest that forced redirection of gene-regulatory elements may be used to alter gene expression to treat disease. |
| first_indexed | 2024-04-10T10:03:32Z |
| format | Article |
| id | doaj.art-32788d42c8a3431085e1147f913baa4b |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-04-10T10:03:32Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-32788d42c8a3431085e1147f913baa4b2023-02-16T04:18:04ZengElsevierMolecular Therapy: Nucleic Acids2162-25312023-03-0131452465Forced enhancer-promoter rewiring to alter gene expression in animal modelsScott A. Peslak0Selami Demirci1Vemika Chandra2Byoung Ryu3Saurabh K. Bhardwaj4Jing Jiang5Jeremy W. Rupon6Robert E. Throm7Naoya Uchida8Alexis Leonard9Khaled Essawi10Aylin C. Bonifacino11Allen E. Krouse12Nathaniel S. Linde13Robert E. Donahue14Francesca Ferrara15Matthew Wielgosz16Osheiza Abdulmalik17Nicole Hamagami18Paula Germino-Watnick19Anh Le20Rebecca Chu21Malikiya Hinds22Mitchell J. Weiss23Wei Tong24John F. Tisdale25Gerd A. Blobel26Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USACellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institutes (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USADivision of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USADepartment of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADivision of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USADivision of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; CAS Engineering Laboratory for Nanozyme, Institute of Biophysics, Chinese Academy of Sciences, Beijing, People’s Republic of ChinaDivision of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USADepartment of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USACellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institutes (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Division of Molecular and Medical Genetics, Center for Gene and Cell Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, JapanCellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institutes (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USACellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institutes (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Department of Medical Laboratory Science, College of Applied Medical Sciences, Jazan University, Jazan, Saudi ArabiaTranslational Stem Cell Biology Branch, NHLBI, NIH, Bethesda, MD 20814, USATranslational Stem Cell Biology Branch, NHLBI, NIH, Bethesda, MD 20814, USATranslational Stem Cell Biology Branch, NHLBI, NIH, Bethesda, MD 20814, USACellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institutes (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USADepartment of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADivision of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USADivision of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USACellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institutes (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USACellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institutes (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USACellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institutes (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USACellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institutes (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USADepartment of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADivision of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USACellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institutes (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Corresponding author John F. Tisdale, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institutes (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.Division of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Corresponding author Gerd A. Blobel, Division of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.Transcriptional enhancers can be in physical proximity of their target genes via chromatin looping. The enhancer at the β-globin locus (locus control region [LCR]) contacts the fetal-type (HBG) and adult-type (HBB) β-globin genes during corresponding developmental stages. We have demonstrated previously that forcing proximity between the LCR and HBG genes in cultured adult-stage erythroid cells can activate HBG transcription. Activation of HBG expression in erythroid cells is of benefit to patients with sickle cell disease. Here, using the β-globin locus as a model, we provide proof of concept at the organismal level that forced enhancer rewiring might present a strategy to alter gene expression for therapeutic purposes. Hematopoietic stem and progenitor cells (HSPCs) from mice bearing human β-globin genes were transduced with lentiviral vectors expressing a synthetic transcription factor (ZF-Ldb1) that fosters LCR-HBG contacts. When engrafted into host animals, HSPCs gave rise to adult-type erythroid cells with elevated HBG expression. Vectors containing ZF-Ldb1 were optimized for activity in cultured human and rhesus macaque erythroid cells. Upon transplantation into rhesus macaques, erythroid cells from HSPCs expressing ZF-Ldb1 displayed elevated HBG production. These findings in two animal models suggest that forced redirection of gene-regulatory elements may be used to alter gene expression to treat disease.http://www.sciencedirect.com/science/article/pii/S2162253123000197MT: OligonucleotidesTherapies and Applicationsenhancer-promoter interactionsforced chromatin loopingsickle cell diseasehemoglobin switching |
| spellingShingle | Scott A. Peslak Selami Demirci Vemika Chandra Byoung Ryu Saurabh K. Bhardwaj Jing Jiang Jeremy W. Rupon Robert E. Throm Naoya Uchida Alexis Leonard Khaled Essawi Aylin C. Bonifacino Allen E. Krouse Nathaniel S. Linde Robert E. Donahue Francesca Ferrara Matthew Wielgosz Osheiza Abdulmalik Nicole Hamagami Paula Germino-Watnick Anh Le Rebecca Chu Malikiya Hinds Mitchell J. Weiss Wei Tong John F. Tisdale Gerd A. Blobel Forced enhancer-promoter rewiring to alter gene expression in animal models Molecular Therapy: Nucleic Acids MT: Oligonucleotides Therapies and Applications enhancer-promoter interactions forced chromatin looping sickle cell disease hemoglobin switching |
| title | Forced enhancer-promoter rewiring to alter gene expression in animal models |
| title_full | Forced enhancer-promoter rewiring to alter gene expression in animal models |
| title_fullStr | Forced enhancer-promoter rewiring to alter gene expression in animal models |
| title_full_unstemmed | Forced enhancer-promoter rewiring to alter gene expression in animal models |
| title_short | Forced enhancer-promoter rewiring to alter gene expression in animal models |
| title_sort | forced enhancer promoter rewiring to alter gene expression in animal models |
| topic | MT: Oligonucleotides Therapies and Applications enhancer-promoter interactions forced chromatin looping sickle cell disease hemoglobin switching |
| url | http://www.sciencedirect.com/science/article/pii/S2162253123000197 |
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