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Cell Death Differ. 2019 May 7. doi: 10.1038/s41418-019-0333-6. [Epub ahead of print]

Chromatin remodellers Brg1 and Bptf are required for normal gene expression and progression of oncogenic Braf-driven mouse melanoma.

Author information

1
Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UNISTRA, 1 Rue Laurent Fries, 67404, Illkirch Cédex, France.
2
INSERM U1021, Normal and Pathological Development of Melanocytes, Institut Curie, PSL Research University, Orsay, France.
3
Univ. Paris-Sud, Univ. Paris-Saclay, CNRS UMR3347, Orsay, France.
4
Equipes Labellisées Ligue Contre le Cancer, Paris, France.
5
Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UNISTRA, 1 Rue Laurent Fries, 67404, Illkirch Cédex, France. irwin@igbmc.fr.
6
Equipes Labellisées Ligue Contre le Cancer, Paris, France. irwin@igbmc.fr.

Abstract

Somatic oncogenic mutation of BRAF coupled with inactivation of PTEN constitute a frequent combination of genomic alterations driving the development of human melanoma. Mice genetically engineered to conditionally express oncogenic BrafV600E and inactivate Pten in melanocytes following tamoxifen treatment rapidly develop melanoma. While early-stage melanomas comprised melanin-pigmented Mitf and Dct-expressing cells, expression of these and other melanocyte identity genes was lost in later stage tumours that showed histological and molecular characteristics of de-differentiated neural crest type cells. Melanocyte identity genes displayed loss of active chromatin marks and RNA polymerase II and gain of heterochromatin marks, indicating epigenetic reprogramming during tumour progression. Nevertheless, late-stage tumour cells grown in culture re-expressed Mitf, and melanocyte markers and Mitf together with Sox10 coregulated a large number of genes essential for their growth. In this melanoma model, somatic inactivation that the catalytic Brg1 (Smarca4) subunit of the SWI/SNF complex and the scaffolding Bptf subunit of the NuRF complex delayed tumour formation and deregulated large and overlapping gene expression programs essential for normal tumour cell growth. Moreover, we show that Brg1 and Bptf coregulated many genes together with Mitf and Sox10. Together these transcription factors and chromatin remodelling complexes orchestrate essential gene expression programs in mouse melanoma cells.

PMID:
31065107
DOI:
10.1038/s41418-019-0333-6

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