More than 10(9) base pairs of the genome in higher eucaryotes are positioned in the interphase nucleus such that gene activation, gene repression, remote gene regulation by enhancer elements, and reading as well as adjusting epigenetic marks are possible. One important structural and functional component of chromatin organization is the zinc finger factor CTCF. Two decades of research has advanced the understanding of the fundamental role that CTCF plays in regulating such a vast expanse of DNA.
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Cells Dev
December 2024
Center for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS, INSERM, Université PSL, Paris, France; School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
2024 not only marked the 100th anniversary of the discovery of the organizer by Hilde Pröscholdt-Mangold and Hans Spemann, but also the 40th anniversary of the discovery of the homeobox, a DNA region encoding a DNA binding peptide present in several transcription factors of critical importance for the gastrulating embryo. In particular, this sequence is found in the 39 members of the amniote Hox gene family, a series of genes activated in mid-gastrulation and involved in organizing morphologies along the extending anterior to posterior (AP) body axis. Over the past 30 years, the study of their coordinated regulation in various contexts has progressively revealed their surprising regulatory strategies, based on mechanisms acting in-cis, which can translate a linear distribution of series of genes along the chromatin fiber into the proper sequences of morphologies observed along our various body axes.
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Nucleic Acids Res
December 2024
NCMIS, CEMS, RCSDS, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, 55 Zhongguancun East Road, Haidian District, Beijing 100190, China.
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Mol Cell
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Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. Electronic address:
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iScience
December 2024
Center for Comparative Biomedicine, Ministry of Education Key Laboratory of Systems Biomedicine, State Key Laboratory of Medical Genomics, Institute of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
As an essential regulator of higher-order chromatin structures, CCCTC-binding factor (CTCF) is a highly conserved protein with a central DNA-binding domain of 11 tandem zinc fingers (ZFs), which are flanked by amino (N-) and carboxy (C-) terminal domains of intrinsically disordered regions. Here we report that CRISPR deletion of the entire C-terminal domain of alternating charge blocks decreases CTCF DNA binding but deletion of the C-terminal fragment of 116 amino acids results in increased CTCF DNA binding and aberrant gene regulation. Through a series of genetic targeting experiments, in conjunction with electrophoretic mobility shift assay (EMSA), circularized chromosome conformation capture (4C), qPCR, chromatin immunoprecipitation with sequencing (ChIP-seq), and assay for transposase-accessible chromatin with sequencing (ATAC-seq), we uncovered a negatively charged region (NCR) responsible for weakening CTCF DNA binding and chromatin accessibility.
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State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai, China.
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