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 PMID:29875417  

SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub.

Rocco Piazza | Vera Magistroni | Sara Redaelli | Mario Mauri | Luca Massimino | Alessandro Sessa | Marco Peronaci | Maciej Lalowski | Rabah Soliymani | Caterina Mezzatesta | Alessandra Pirola | Federica Banfi | Alicia Rubio | Delphine Rea | Fabio Stagno | Emilio Usala | Bruno Martino | Leonardo Campiotti | Michele Merli | Francesco Passamonti | Francesco Onida | Alessandro Morotti | Francesca Pavesi | Marco Bregni | Vania Broccoli | Marc Baumann | Carlo Gambacorti-Passerini
Nature communications | 2018

SETBP1 variants occur as somatic mutations in several hematological malignancies such as atypical chronic myeloid leukemia and as de novo germline mutations in the Schinzel-Giedion syndrome. Here we show that SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of gene expression through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex. Deletion of two AT-hooks abrogates the binding of SETBP1 to gDNA and impairs target gene upregulation. Genes controlled by SETBP1 such as MECOM are significantly upregulated in leukemias containing SETBP1 mutations. Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis. In line with these findings, in utero brain electroporation of mutated SETBP1 causes impairment of mouse neurogenesis with a profound delay in neuronal migration. In summary, this work unveils a SETBP1 function that directly affects gene transcription and clarifies the mechanism operating in myeloid malignancies and in the Schinzel-Giedion syndrome caused by SETBP1 mutations.

Pubmed ID: 29875417

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RRID:SCR_001672

Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.

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