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 PassamontiFrancesco Onida, Alessandro Morotti, Francesca Pavesi, Marco Bregni, Vania Broccoli, Marc Baumann, Carlo Gambacorti-Passerini

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number2192
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Piazza, R., Magistroni, V., Redaelli, S., Mauri, M., Massimino, L., Sessa, A., Peronaci, M., Lalowski, M., Soliymani, R., Mezzatesta, C., Pirola, A., Banfi, F., Rubio, A., Rea, D., Stagno, F., Usala, E., Martino, B., Campiotti, L., Merli, M., ... Gambacorti-Passerini, C. (2018). SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub. Nature Communications, 9(1), [2192]. https://doi.org/10.1038/s41467-018-04462-8