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Deletion of a single CTCF motif at the boundary of a chromatin domain with three FGF genes disrupts gene expression and embryonic development

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Developmental Cell 2025年

作者： Chakraborty, Shreeta Wenzlitschke, Nina Anderson, Matthew J. Eraso, Ariel Baudic, Manon Thompson, Joyce J. Evans, Alicia A. Shatford-Adams, Lilly M. Chari, Raj Awasthi, Parirokh Dale, Ryan K. Lewandoski, Mark Petros, Timothy J. Rocha, Pedro P. Unit on Genome Structure and Regulation National Institute of Child Health and Human Development National Institutes of Health Bethesda 20892 MD United States Genetics of Vertebrate Development Section Cancer and Developmental Biology Laboratory National Cancer Institute National Institutes of Health Frederick 21702 MD United States Bioinformatics and Scientific Programming Core National Institute of Child Health and Human Development National Institutes of Health Bethesda 20892 MD United States Laboratory Animal Sciences Program Frederick National Laboratory for Cancer Research Frederick 21702 MD United States Unit on Cellular and Molecular Neurodevelopment National Institute of Child Health and Human Development National Institutes of Health Bethesda 20892 MD United States National Cancer Institute NIH Bethesda 20892 MD United States

Chromatin domains delimited by CTCF can restrict the range of enhancer action. However, disruption of some domain boundaries results in mild gene dysregulation and phenotypes. We tested whether perturbing a domain with multiple developmental regulators would lead to more severe outcomes. We chose a domain with three FGF ligand genes—Fgf3, Fgf4, and Fgf15—that control different murine developmental processes. Heterozygous deletion of a 23.9-kb boundary defined by four CTCF sites led to ectopic interactions of the FGF genes with enhancers active in the brain and induced FGF expression. This caused orofacial clefts, encephalocele, and fully penetrant perinatal lethality. Loss of the single CTCF motif oriented toward the enhancers—but not the three toward the FGF genes—recapitulated these phenotypes. Our works shows that small sequence variants at particular domain boundaries can have a surprisingly outsized effect and must be considered as potential sources of gene dysregulation in development and disease. © 2025

关键词： CTCF epigenetics FGF gene regulation nuclear organization

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Parp1 deletion rescues cerebellar hypotrophy in xrcc1 mutant zebrafish

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scientific Reports 2025年第1期15卷 1-8页

作者： Semenova, Svetlana A. Nammi, Deepthi Garrett, Grace B. Margolin, Gennady Sinclair, Jennifer L. Maroofian, Reza Caldecott, Keith W. Burgess, Harold A. Division of Developmental Biology Eunice Kennedy Shriver National Institute of Child Health and Human Development Bethesda 20892 MD United States Bioinformatics and Scientific Programming Core Eunice Kennedy Shriver National Institute of Child Health and Human Development Bethesda 20892 MD United States Department of Neuromuscular Disorders UCL Queen Square Institute of Neurology University College London London United Kingdom Genome Damage and Stability Centre School of Life Sciences University of Sussex Brighton United Kingdom

Defects in DNA single-strand break repair are associated with neurodevelopmental and neurodegenerative disorders. One such disorder is that resulting from mutations in XRCC1, a scaffold protein that plays a central role in DNA single-strand base repair. XRCC1 is recruited at sites of single-strand breaks by PARP1, a protein that detects and is activated by such breaks and is negatively regulated by XRCC1 to prevent excessive PARP binding and activity. Loss of XRCC1 leads to the toxic accumulation and activity of PARP1 at single-strand breaks leading to base excision repair defects, a mechanism that may underlie pathological changes in patients carrying deleterious XRCC1 mutations. Here, we demonstrate that xrcc1 knockdown impairs development of the cerebellar plate in zebrafish. In contrast, parp1 knockdown alone does not significantly affect neural development, and instead rescues the cerebellar defects observed in xrcc1 mutant larvae. These findings support the notion that PARP1 inhibition may be a viable therapeutic candidate in neurological disorders. © This is a U.S. Government work and not under copyright protection in the US;foreign copyright protection may apply 2025.

关键词： Cerebellar development parp1 xrcc1 Zebrafish

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The role of TMEM38B in OI osteoblasts differentiation and mineralization

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Bone Reports 2022年 16卷

作者： Milena Jovanovic Apratim Mitra Ryan K. Dale Joan C. Marini NICHD/NIH Heritable Disorders of Bone and Extracellular Matrix Bethesda United States NICHD/NIH Bioinformatics and Scientific Programming Core Bethesda United States

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Insight into the bone dysplasia mechanism of CRTAP-null osteoblasts

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Bone Reports 2022年 16卷

作者： Aileen Barnes Apratim Mitra Ryan Dale Joan Marini NICHD/NIH Section on Heritable Disorders of Bone and Extracellular Matrix Bethesda United States NICHD/NIH Bioinformatics & Scientific Programming Core Bethesda United States NICHD/NIH Computer Support Services Core Bethesda United States

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Studies of OI patient and murine osteoblasts to investigate phenotypic variability of dominant Osteogenesis Imperfecta

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Bone Reports 2021年 14卷

作者： Milena Jovanovic Apratim Mitra Chris Stephan Kenneth Kozloff Ryan Dale Joan C. Marini NICHD/NIH Heritable Disorders of Bone and Extracellular Matrix Bethesda United States NICHD/NIH Bioinformatics and Scientific Programming Core Bethesda United States University of Michigan Department of Orthopaedic Surgery Ann Arbor United States

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Author Correction: Anchoring cortical granules in the cortex ensures trafficking to the plasma membrane for post-fertilization exocytosis

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Nature communications 2019年第1期10卷 2926页

作者： Edgar-John Vogt Keizo Tokuhiro Min Guo Ryan Dale Guanghui Yang Seung-Wook Shin Maria Jimenez Movilla Hari Shroff Jurrien Dean Laboratory of Cellular and Developmental Biology NIDDK National Institutes of Health Bethesda MD 20892 USA. Charité - Universitätsmedizin Berlin Augustenburger Platz 1 13353 Berlin Germany. Department of Genome Editing Institute of Biomedical Science Kansai Medical University 2-5-1 Shinmachi Hirakata Osaka 573-1010 Japan. Section on High Resolution Optical Imaging NIBIB National Institutes of Health Bethesda MD 20892 USA. Bioinformatics and Scientific Programming Core Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD 20892 USA. Department of Cell Biology and Histology Medical School University of Murcia IMIB 30100 Murcia Spain. Advanced Imaging and Microscopy Resource National Institutes of Health Bethesda MD 20892 USA. Laboratory of Cellular and Developmental Biology NIDDK National Institutes of Health Bethesda MD 20892 USA. jurrien.dean@nih.gov.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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