Dissecting the functions of NIPBL using genome editing: The importance of the N-terminus of NIPBL in transcriptional regulation
Dissecting the functions of NIPBL using genome editing: The importance of the N-terminus of NIPBL in transcriptional regulation
ABSTRACT Cornelia de Lange syndrome (CdLS) is characterized by craniofacial dysmorphisms, intellectual disabilities, growth retardation, and several other systemic abnormalities. CdLS is caused by heterozygous germline mutations in structural and regulatory components of cohesin. Mutations in NIPBL, which encodes regulatory subunit of cohesin, are frequently found in individuals with CdLS. CdLS is associated with a currently unknown mechanism of global transcriptional dysregulation. In this study, NIPBL mutants were generated using the CRISPR/Cas9 system to study this mechanism. Clones with a biallelic frameshift mutation in exon 3 of NIPBL, resulting in a truncated N-terminus, displayed transcriptional dysregulation without sister chromatid separation defects. Detailed transcriptome analysis revealed the overexpression of genes in NIPBL mutants that are typically expressed at low levels in wild type and the reduced expression of genes that are typically expressed at high levels in wild type. This result suggested that NIPBL plays a role in fine-tuning gene expression levels. MAU2 protein, that closely interacts with NIPBL, was nearly absent in these clones. The reduction of MAU2 observed in NIPBL mutants points to the importance of the NIPBL N-terminus/MAU2 interaction in transcriptional regulatory role of NIPBL.
Shirahige Katsuhiko、Otsubo Aiko、Akiyama Kazuhiro、Masuda Koji、Nakato Ryuichiro、Izumi Kosuke、Fujiki Katsunori、Bando Masashige
Research Center for Epigenetic Disease, Institute for Quantitative Biosciences, The University of TokyoDivision of Human Genetics, Department of Pediatrics, The Children?ˉs Hospital of PhiladelphiaResearch Center for Epigenetic Disease, Institute for Quantitative Biosciences, The University of TokyoResearch Center for Epigenetic Disease, Institute for Quantitative Biosciences, The University of TokyoResearch Center for Epigenetic Disease, Institute for Quantitative Biosciences, The University of TokyoResearch Center for Epigenetic Disease, Institute for Quantitative Biosciences, The University of Tokyo||Division of Human Genetics, Department of Pediatrics, The Children?ˉs Hospital of PhiladelphiaResearch Center for Epigenetic Disease, Institute for Quantitative Biosciences, The University of TokyoResearch Center for Epigenetic Disease, Institute for Quantitative Biosciences, The University of Tokyo
基础医学遗传学分子生物学
Shirahige Katsuhiko,Otsubo Aiko,Akiyama Kazuhiro,Masuda Koji,Nakato Ryuichiro,Izumi Kosuke,Fujiki Katsunori,Bando Masashige.Dissecting the functions of NIPBL using genome editing: The importance of the N-terminus of NIPBL in transcriptional regulation[EB/OL].(2025-03-28)[2025-05-25].https://www.biorxiv.org/content/10.1101/616086.点此复制
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