SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub
Articolo
Data di Pubblicazione:
2018
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
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
Abnormalities, Multiple; Animals; Brain; Carrier Proteins; Cell Line, Tumor; Craniofacial Abnormalities; Gene Ontology; HEK293 Cells; Hand Deformities, Congenital; Humans; Intellectual Disability; Leukemia; Mice; Nails, Malformed; Neurogenesis; Nuclear Proteins; Promoter Regions, Genetic; Protein Binding; Epigenesis, Genetic; Gene Expression Profiling; Mutation
Elenco autori:
Piazza, Rocco; Magistroni, Vera; Redaelli, Sara; Mauri, Mario; Massimino, Luca; Sessa, Alessandro; Peronaci, Marco; Lalowski, Maciej; Soliymani, Rabah; Mezzatesta, Caterina; Pirola, Alessandra; Banfi, Federica; Rubio, Alicia; Rea, Delphine; Stagno, Fabio; Usala, Emilio; Martino, Bruno; Campiotti, Leonardo; Merli, Michele; Passamonti, Francesco; Onida, Francesco; Morotti, Alessandro; Pavesi, Francesca; Bregni, Marco; Broccoli, Vania; Baumann, Marc; Gambacorti-Passerini, Carlo
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