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 and Carlo Gambacorti-Passerini
Additional contact information
Rocco Piazza: University of Milano-Bicocca and San Gerardo hospital
Vera Magistroni: University of Milano-Bicocca and San Gerardo hospital
Sara Redaelli: University of Milano-Bicocca and San Gerardo hospital
Mario Mauri: University of Milano-Bicocca and San Gerardo hospital
Luca Massimino: University of Milano-Bicocca and San Gerardo hospital
Alessandro Sessa: San Raffaele Scientific Institute
Marco Peronaci: University of Milano-Bicocca and San Gerardo hospital
Maciej Lalowski: University of Helsinki
Rabah Soliymani: University of Helsinki
Caterina Mezzatesta: University of Milano-Bicocca and San Gerardo hospital
Alessandra Pirola: University of Milano-Bicocca and San Gerardo hospital
Federica Banfi: San Raffaele Scientific Institute
Alicia Rubio: San Raffaele Scientific Institute
Delphine Rea: Hôpital Saint-Louis
Fabio Stagno: AOU Policlinico
Emilio Usala: Ospedale Businco
Bruno Martino: UO Ematologia Azienda Ospedaliera “BIANCHI MELACRINO MORELLI”
Leonardo Campiotti: Università Insubria
Michele Merli: University Hospital Ospedale di Circolo e Fondazione Macchi
Francesco Passamonti: University of Varese
Francesco Onida: University of Milan
Alessandro Morotti: University of Torino
Francesca Pavesi: IRCCS San Raffaele Scientific Institute
Marco Bregni: Ospedale di Circolo di Busto Arsizio
Vania Broccoli: San Raffaele Scientific Institute
Marc Baumann: University of Helsinki
Carlo Gambacorti-Passerini: University of Milano-Bicocca and San Gerardo hospital

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04462-8

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DOI: 10.1038/s41467-018-04462-8

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