Bromodomain and extra-terminal domain (BET) proteins regulate melanocyte differentiation.
Cell Cycle Proteins
/ genetics
Cell Differentiation
Cells, Cultured
HEK293 Cells
Humans
Melanins
/ biosynthesis
Melanocytes
/ cytology
Membrane Glycoproteins
/ genetics
Microphthalmia-Associated Transcription Factor
/ metabolism
Monophenol Monooxygenase
/ genetics
Oxidoreductases
/ genetics
Promoter Regions, Genetic
Protein Binding
Transcription Factors
/ genetics
BET
BRD4
Bromodomain and extra-terminal domain
ChIP-Seq
Epigenomics
JQ1
MITF
Melanocyte differentiation
Melanoma
Pigmentation
Systems biology
Transcriptional networks
Journal
Epigenetics & chromatin
ISSN: 1756-8935
Titre abrégé: Epigenetics Chromatin
Pays: England
ID NLM: 101471619
Informations de publication
Date de publication:
10 03 2020
10 03 2020
Historique:
received:
21
08
2019
accepted:
19
02
2020
entrez:
11
3
2020
pubmed:
11
3
2020
medline:
22
4
2021
Statut:
epublish
Résumé
Pharmacologic inhibition of bromodomain and extra-terminal (BET) proteins is currently being explored as a new therapeutic approach in cancer. Some studies have also implicated BET proteins as regulators of cell identity and differentiation through their interactions with lineage-specific factors. However, the role of BET proteins has not yet been investigated in melanocyte differentiation. Melanocyte inducing transcription factor (MITF) is the master regulator of melanocyte differentiation, essential for pigmentation and melanocyte survival. In this study, we tested the hypothesis that BET proteins regulate melanocyte differentiation through interactions with MITF. Here we show that chemical inhibition of BET proteins prevents differentiation of unpigmented melanoblasts into pigmented melanocytes and results in de-pigmentation of differentiated melanocytes. BET inhibition also slowed cell growth, without causing cell death, increasing the number of cells in G1. Transcriptional profiling revealed that BET inhibition resulted in decreased expression of pigment-specific genes, including many MITF targets. The expression of pigment-specific genes was also down-regulated in melanoma cells, but to a lesser extent. We found that RNAi depletion of the BET family members, bromodomain-containing protein 4 (BRD4) and bromodomain-containing protein 2 (BRD2) inhibited expression of two melanin synthesis enzymes, TYR and TYRP1. Both BRD4 and BRD2 were detected on melanocyte promoters surrounding MITF-binding sites, were associated with open chromatin structure, and promoted MITF binding to these sites. Furthermore, BRD4 and BRD2 physically interacted with MITF. These findings indicate a requirement for BET proteins in the regulation of pigmentation and melanocyte differentiation. We identified changes in pigmentation specific gene expression that occur upon BET inhibition in melanoblasts, melanocytes, and melanoma cells.
Sections du résumé
BACKGROUND
Pharmacologic inhibition of bromodomain and extra-terminal (BET) proteins is currently being explored as a new therapeutic approach in cancer. Some studies have also implicated BET proteins as regulators of cell identity and differentiation through their interactions with lineage-specific factors. However, the role of BET proteins has not yet been investigated in melanocyte differentiation. Melanocyte inducing transcription factor (MITF) is the master regulator of melanocyte differentiation, essential for pigmentation and melanocyte survival. In this study, we tested the hypothesis that BET proteins regulate melanocyte differentiation through interactions with MITF.
RESULTS
Here we show that chemical inhibition of BET proteins prevents differentiation of unpigmented melanoblasts into pigmented melanocytes and results in de-pigmentation of differentiated melanocytes. BET inhibition also slowed cell growth, without causing cell death, increasing the number of cells in G1. Transcriptional profiling revealed that BET inhibition resulted in decreased expression of pigment-specific genes, including many MITF targets. The expression of pigment-specific genes was also down-regulated in melanoma cells, but to a lesser extent. We found that RNAi depletion of the BET family members, bromodomain-containing protein 4 (BRD4) and bromodomain-containing protein 2 (BRD2) inhibited expression of two melanin synthesis enzymes, TYR and TYRP1. Both BRD4 and BRD2 were detected on melanocyte promoters surrounding MITF-binding sites, were associated with open chromatin structure, and promoted MITF binding to these sites. Furthermore, BRD4 and BRD2 physically interacted with MITF.
CONCLUSION
These findings indicate a requirement for BET proteins in the regulation of pigmentation and melanocyte differentiation. We identified changes in pigmentation specific gene expression that occur upon BET inhibition in melanoblasts, melanocytes, and melanoma cells.
Identifiants
pubmed: 32151278
doi: 10.1186/s13072-020-00333-z
pii: 10.1186/s13072-020-00333-z
pmc: PMC7063807
doi:
Substances chimiques
BRD2 protein, human
0
BRD4 protein, human
0
Cell Cycle Proteins
0
MITF protein, human
0
Melanins
0
Membrane Glycoproteins
0
Microphthalmia-Associated Transcription Factor
0
Transcription Factors
0
Oxidoreductases
EC 1.-
TYRP1 protein, human
EC 1.14.18.-
Monophenol Monooxygenase
EC 1.14.18.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
14Subventions
Organisme : NCI NIH HHS
ID : R00 CA154887
Pays : United States
Organisme : Melanoma Research Foundation
ID : 126948
Pays : International
Organisme : NIAMS NIH HHS
ID : R01AR059379
Pays : United States
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