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Nat Commun. 2018 Jun 6;9(1):2192. doi: 10.1038/s41467-018-04462-8.

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

Author information

1
Department of Medicine and Surgery, University of Milano-Bicocca and San Gerardo hospital, 20900, Monza, Italy. rocco.piazza@unimib.it.
2
Department of Medicine and Surgery, University of Milano-Bicocca and San Gerardo hospital, 20900, Monza, Italy.
3
Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132, Milan, Italy.
4
Department of Biochemistry and Developmental Biology, Faculty of Medicine, Meilahti Clinical Proteomics Core Facility, University of Helsinki, 00290, Helsinki, Finland.
5
Service d'Hématologie Adulte, Hôpital Saint-Louis, 75010, Paris, France.
6
Chair and Hematology Section, Ferrarotto Hospital, AOU Policlinico, 95123, Catania, Italy.
7
Azienda Brotzu U.O. Ematologia e CTMO, Ospedale Businco, 09121, Cagliari, Italy.
8
UO Ematologia Azienda Ospedaliera "BIANCHI MELACRINO MORELLI", 89124, Reggio Calabria, Italy.
9
Dipartimento Medicina Clinica e Sperimentale, Università Insubria, 21100, Varese, Italy.
10
Division of Hematology, University Hospital Ospedale di Circolo e Fondazione Macchi, 21100, Varese, Italy.
11
Hematology, Dipartimento di Medicina Clinica e Sperimentale, University of Varese, 21100, Varese, Italy.
12
BMT Center - Oncohematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, 20122, Milan, Italy.
13
Department of Clinical and Biological Sciences, University of Torino, 10043, Orbassano (Torino), Italy.
14
Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy.
15
Oncology Unit, ASST Valle Olona, Ospedale di Circolo di Busto Arsizio, 21052, Busto Arsizio, Italy.
16
CNR Institute of Neuroscience, 20129, Milan, Italy.

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.

PMID:
29875417
PMCID:
PMC5989213
DOI:
10.1038/s41467-018-04462-8
[Indexed for MEDLINE]
Free PMC Article

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