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Epigenetic and pharmacological control of pigmentation via Bromodomain Protein 9 (BRD9).
Pigment Cell Melanoma Res. 36, 19-32 (2023)
Lineage-specific differentiation programs are activated by epigenetic changes in chromatin structure. Melanin-producing melanocytes maintain a gene expression program ensuring appropriate enzymatic conversion of metabolites into the pigment, melanin, and transfer to surrounding cells. During neuroectodermal development, SMARCA4 (BRG1), the catalytic subunit of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes, is essential for lineage specification. SMARCA4 is also required for development of multipotent neural crest precursors into melanoblasts, which differentiate into pigment-producing melanocytes. In addition to the catalytic domain, SMARCA4 and several SWI/SNF subunits contain bromodomains which are amenable to pharmacological inhibition. We investigated the effects of pharmacological inhibitors of SWI/SNF bromodomains on melanocyte differentiation. Strikingly, treatment of murine melanoblasts and human neonatal epidermal melanocytes with selected bromodomain inhibitors abrogated melanin synthesis and visible pigmentation. Using functional genomics, iBRD9, a small molecule selective for the bromodomain of BRD9 was found to repress pigmentation-specific gene expression. Depletion of BRD9 confirmed a requirement for expression of pigmentation genes in the differentiation program from melanoblasts into pigmented melanocytes and in melanoma cells. Chromatin immunoprecipitation assays showed that iBRD9 disrupts the occupancy of BRD9 and the catalytic subunit SMARCA4 at melanocyte-specific loci. These data indicate that BRD9 promotes melanocyte pigmentation whereas pharmacological inhibition of BRD9 is repressive.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Brd9 ; Swi/snf ; Bromodomain ; Chromatin Remodeling ; Epigenetic ; Melanocyte Differentiation ; Melanoma ; Pigmentation
Language
english
Publication Year
2023
Prepublished in Year
2022
HGF-reported in Year
2022
ISSN (print) / ISBN
1755-1471
e-ISSN
1755-148X
Journal
Pigment Cell & Melanoma Research
Quellenangaben
Volume: 36,
Issue: 1,
Pages: 19-32
Publisher
Wiley
Reviewing status
Peer reviewed
Institute(s)
Institute of Computational Biology (ICB)
POF-Topic(s)
30205 - Bioengineering and Digital Health
Research field(s)
Enabling and Novel Technologies
PSP Element(s)
G-503800-001
Grants
Melanoma Research Foundation
WOS ID
WOS:000864144500001
Scopus ID
85139192033
PubMed ID
36112085
Erfassungsdatum
2022-11-24