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Article ; Online: Molecular Architecture of the Essential Yeast Histone Acetyltransferase Complex NuA4 Redefines Its Multimodularity.

Setiaputra, Dheva / Ahmad, Salar / Dalwadi, Udit / Steunou, Anne-Lise / Lu, Shan / Ross, James D / Dong, Meng-Qiu / Côté, Jacques / Yip, Calvin K

Molecular and cellular biology

2018 Volume 38, Issue 9

Abstract: Conserved from yeast to humans, the NuA4 histone acetyltransferase is a large multisubunit complex essential for cell viability through the regulation of gene expression, genome maintenance, metabolism, and cell fate during development and stress. How ... ...

Abstract	Conserved from yeast to humans, the NuA4 histone acetyltransferase is a large multisubunit complex essential for cell viability through the regulation of gene expression, genome maintenance, metabolism, and cell fate during development and stress. How the different NuA4 subunits work in concert with one another to perform these diverse functions remains unclear, and addressing this central question requires a comprehensive understanding of NuA4's molecular architecture and subunit organization. We have determined the structure of fully assembled native yeast NuA4 by single-particle electron microscopy. Our data revealed that NuA4 adopts a trilobal overall architecture, with each of the three lobes constituted by one or two functional modules. By performing cross-linking coupled to mass spectrometry analysis and
MeSH term(s)	Acetylation ; Amino Acid Sequence ; Histone Acetyltransferases/genetics ; Histone Acetyltransferases/metabolism ; Histone Acetyltransferases/ultrastructure ; Histones ; Microscopy, Electron/methods ; Nucleosomes/physiology ; Protein Subunits/chemistry ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Saccharomyces cerevisiae Proteins/ultrastructure
Chemical Substances	Histones ; Nucleosomes ; Protein Subunits ; Saccharomyces cerevisiae Proteins ; Histone Acetyltransferases (EC 2.3.1.48) ; NuA4 protein, S cerevisiae (EC 2.3.1.48)
Language	English
Publishing date	2018-04-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00570-17
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Article ; Online: Molecular Architecture of the Essential Yeast Histone Acetyltransferase Complex NuA4 Redefines Its Multimodularity

Setiaputra, Dheva / Ahmad, Salar / Dalwadi, Udit / Steunou, Anne-Lise / Lu, Shan / Ross, James D. / Dong, Meng-Qiu / Côté, Jacques / Yip, Calvin K.

Molecular and Cellular Biology. 2018 May 1, v. 38, no. 9 p.e00570-17-

2018

Abstract	Conserved from yeast to humans, the NuA4 histone acetyltransferase is a large multisubunit complex essential for cell viability through the regulation of gene expression, genome maintenance, metabolism, and cell fate during development and stress. How the different NuA4 subunits work in concert with one another to perform these diverse functions remains unclear, and addressing this central question requires a comprehensive understanding of NuA4's molecular architecture and subunit organization. We have determined the structure of fully assembled native yeast NuA4 by single-particle electron microscopy. Our data revealed that NuA4 adopts a trilobal overall architecture, with each of the three lobes constituted by one or two functional modules. By performing cross-linking coupled to mass spectrometry analysis and in vitro protein interaction studies, we further mapped novel intermolecular interfaces within NuA4. Finally, we combined these new data with other known structural information of NuA4 subunits and subassemblies to construct a multiscale model to illustrate how the different NuA4 subunits and modules are spatially arranged. This model shows that the multiple chromatin reader domains are clustered together around the catalytic core, suggesting that NuA4's multimodular architecture enables it to engage in multivalent interactions with its nucleosome substrate.
Keywords	cell viability ; crosslinking ; electron microscopy ; gene expression regulation ; genome ; histone acetyltransferase ; mass spectrometry ; metabolism ; models ; nucleosomes ; yeasts ; NuA4 ; cross-linking coupled to mass spectrometry ; yeast
Language	English
Dates of publication	2018-0501
Publishing place	Taylor & Francis
Document type	Article ; Online
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00570-17
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Combined Action of Histone Reader Modules Regulates NuA4 Local Acetyltransferase Function but Not Its Recruitment on the Genome

Steunou, Anne-Lise / Cramet, Myriam / Rossetto, Dorine / Aristizabal, Maria J. / Lacoste, Nicolas / Drouin, Simon / Côté, Valérie / Paquet, Eric / Utley, Rhea T. / Krogan, Nevan / Robert, François / Kobor, Michael S. / Côté, Jacques

Molecular and Cellular Biology. 2016 Nov. 1, v. 36, no. 22 p.2768-2781

2016

Abstract: Recognition of histone marks by reader modules is thought to be at the heart of epigenetic mechanisms. These protein domains are considered to function by targeting regulators to chromosomal loci carrying specific histone modifications. This is important ...

Abstract	Recognition of histone marks by reader modules is thought to be at the heart of epigenetic mechanisms. These protein domains are considered to function by targeting regulators to chromosomal loci carrying specific histone modifications. This is important for proper gene regulation as well as propagation of epigenetic information. The NuA4 acetyltransferase complex contains two of these reader modules, an H3K4me3-specific plant homeodomain (PHD) within the Yng2 subunit and an H3K36me2/3-specific chromodomain in the Eaf3 subunit. While each domain showed a close functional interaction with the respective histone mark that it recognizes, at the biochemical level, genetic level (as assessed with epistatic miniarray profile screens), and phenotypic level, cells with the combined loss of both readers showed greatly enhanced phenotypes. Chromatin immunoprecipitation coupled with next-generation sequencing experiments demonstrated that the Yng2 PHD specifically directs H4 acetylation near the transcription start site of highly expressed genes, while Eaf3 is important downstream on the body of the genes. Strikingly, the recruitment of the NuA4 complex to these loci was not significantly affected. Furthermore, RNA polymerase II occupancy was decreased only under conditions where both PHD and chromodomains were lost, generally in the second half of the gene coding regions. Altogether, these results argue that methylated histone reader modules in NuA4 are not responsible for its recruitment to the promoter or coding regions but, rather, are required to orient its acetyltransferase catalytic site to the methylated histone 3-bearing nucleosomes in the surrounding chromatin, cooperating to allow proper transition from transcription initiation to elongation.
Keywords	DNA-directed RNA polymerase ; acetylation ; acetyltransferases ; active sites ; chromatin immunoprecipitation ; epigenetics ; epistasis ; histones ; methylation ; nucleosomes ; phenotype ; transcription initiation ; transcription initiation site
Language	English
Dates of publication	2016-1101
Size	p. 2768-2781.
Publishing place	Taylor & Francis
Document type	Article ; Online
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00112-16
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Article ; Online: Combined Action of Histone Reader Modules Regulates NuA4 Local Acetyltransferase Function but Not Its Recruitment on the Genome.

Steunou, Anne-Lise / Cramet, Myriam / Rossetto, Dorine / Aristizabal, Maria J / Lacoste, Nicolas / Drouin, Simon / Côté, Valérie / Paquet, Eric / Utley, Rhea T / Krogan, Nevan / Robert, François / Kobor, Michael S / Côté, Jacques

Molecular and cellular biology

2016 Volume 36, Issue 22, Page(s) 2768–2781

Abstract	Recognition of histone marks by reader modules is thought to be at the heart of epigenetic mechanisms. These protein domains are considered to function by targeting regulators to chromosomal loci carrying specific histone modifications. This is important for proper gene regulation as well as propagation of epigenetic information. The NuA4 acetyltransferase complex contains two of these reader modules, an H3K4me3-specific plant homeodomain (PHD) within the Yng2 subunit and an H3K36me2/3-specific chromodomain in the Eaf3 subunit. While each domain showed a close functional interaction with the respective histone mark that it recognizes, at the biochemical level, genetic level (as assessed with epistatic miniarray profile screens), and phenotypic level, cells with the combined loss of both readers showed greatly enhanced phenotypes. Chromatin immunoprecipitation coupled with next-generation sequencing experiments demonstrated that the Yng2 PHD specifically directs H4 acetylation near the transcription start site of highly expressed genes, while Eaf3 is important downstream on the body of the genes. Strikingly, the recruitment of the NuA4 complex to these loci was not significantly affected. Furthermore, RNA polymerase II occupancy was decreased only under conditions where both PHD and chromodomains were lost, generally in the second half of the gene coding regions. Altogether, these results argue that methylated histone reader modules in NuA4 are not responsible for its recruitment to the promoter or coding regions but, rather, are required to orient its acetyltransferase catalytic site to the methylated histone 3-bearing nucleosomes in the surrounding chromatin, cooperating to allow proper transition from transcription initiation to elongation.
MeSH term(s)	Acetylation ; Acetyltransferases/chemistry ; Acetyltransferases/genetics ; Acetyltransferases/metabolism ; Binding Sites ; Catalytic Domain ; Chromatin Immunoprecipitation ; Epigenesis, Genetic ; Genome, Fungal ; High-Throughput Nucleotide Sequencing ; Histone Acetyltransferases/chemistry ; Histone Acetyltransferases/metabolism ; Histone Code ; Histones/metabolism ; Promoter Regions, Genetic ; RNA Polymerase II/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/chemistry ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Sequence Analysis, DNA ; Transcription Initiation Site
Chemical Substances	Histones ; Saccharomyces cerevisiae Proteins ; Acetyltransferases (EC 2.3.1.-) ; Eaf3 protein, S cerevisiae (EC 2.3.1.-) ; Yng2 protein, S cerevisiae (EC 2.3.1.-) ; Histone Acetyltransferases (EC 2.3.1.48) ; NuA4 protein, S cerevisiae (EC 2.3.1.48) ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2016-10-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00112-16
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Article ; Online: Eaf5/7/3 form a functionally independent NuA4 submodule linked to RNA polymerase II-coupled nucleosome recycling.

Rossetto, Dorine / Cramet, Myriam / Wang, Alice Y / Steunou, Anne-Lise / Lacoste, Nicolas / Schulze, Julia M / Côté, Valérie / Monnet-Saksouk, Julie / Piquet, Sandra / Nourani, Amine / Kobor, Michael S / Côté, Jacques

The EMBO journal

2014 Volume 33, Issue 12, Page(s) 1397–1415

Abstract: The NuA4 histone acetyltransferase complex is required for gene regulation, cell cycle progression, and DNA repair. Dissection of the 13-subunit complex reveals that the Eaf7 subunit bridges Eaf5 with Eaf3, a H3K36me3-binding chromodomain protein, and ... ...

Abstract	The NuA4 histone acetyltransferase complex is required for gene regulation, cell cycle progression, and DNA repair. Dissection of the 13-subunit complex reveals that the Eaf7 subunit bridges Eaf5 with Eaf3, a H3K36me3-binding chromodomain protein, and this Eaf5/7/3 trimer is anchored to NuA4 through Eaf5. This trimeric subcomplex represents a functional module, and a large portion exists in a native form outside the NuA4 complex. Gene-specific and genome-wide location analyses indicate that Eaf5/7/3 correlates with transcription activity and is enriched over the coding region. In agreement with a role in transcription elongation, the Eaf5/7/3 trimer interacts with phosphorylated RNA polymerase II and helps its progression. Loss of Eaf5/7/3 partially suppresses intragenic cryptic transcription arising in set2 mutants, supporting a role in nucleosome destabilization. On the other hand, loss of the trimer leads to an increase of replication-independent histone exchange over the coding region of transcribed genes. Taken together, these results lead to a model where Eaf5/7/3 associates with elongating polymerase to promote the disruption of nucleosomes in its path, but also their refolding in its wake.
MeSH term(s)	Acetyltransferases/metabolism ; Blotting, Western ; Chromatin Immunoprecipitation ; Gene Expression Regulation, Fungal/genetics ; Histone Acetyltransferases/metabolism ; Models, Biological ; Multiprotein Complexes/metabolism ; Nucleosomes/physiology ; RNA Polymerase II/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/metabolism
Chemical Substances	Multiprotein Complexes ; Nucleosomes ; Saccharomyces cerevisiae Proteins ; Acetyltransferases (EC 2.3.1.-) ; Eaf3 protein, S cerevisiae (EC 2.3.1.-) ; Eaf5 protein, S cerevisiae (EC 2.3.1.-) ; Eaf7 protein, S cerevisiae (EC 2.3.1.-) ; Histone Acetyltransferases (EC 2.3.1.48) ; NuA4 protein, S cerevisiae (EC 2.3.1.48) ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2014-05-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.201386433
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Zs.A 1808: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Genome-wide analysis of POU3F2/BRN2 promoter occupancy in human melanoma cells reveals Kitl as a novel regulated target gene.

Kobi, Dominique / Steunou, Anne-Lise / Dembélé, Doulaye / Legras, Stéphanie / Larue, Lionel / Nieto, Laurence / Davidson, Irwin

Pigment cell & melanoma research

2010 Volume 23, Issue 3, Page(s) 404–418

Abstract: POU3F2 is a POU-Homeodomain transcription factor expressed in neurons and melanoma cells. In melanoma lesions, cells expressing high levels of POU3F2 show enhanced invasive and metastatic capacity that can in part be explained by repression of ... ...

Abstract	POU3F2 is a POU-Homeodomain transcription factor expressed in neurons and melanoma cells. In melanoma lesions, cells expressing high levels of POU3F2 show enhanced invasive and metastatic capacity that can in part be explained by repression of Micropthalmia-associated Transcription Factor (MITF) expression via POU3F2 binding to its promoter. To identify other POU3F2 target genes that may be involved in modulating the properties of melanoma cells, we performed ChIP-chip experiments in 501Mel melanoma cells. 2108 binding loci located in the regulatory regions of 1700 potential target genes were identified. Bioinformatic and experimental assays showed the presence of known POU3F2-binding motifs, but also many AT-rich sequences with only partial similarity to the known motifs at the occupied loci. Functional analysis indicates that POU3F2 regulates the stem cell factor (Kit ligand, Kitl) promoter via a cluster of four closely spaced binding sites located in the proximal promoter. Our results suggest that POU3F2 may regulate the properties of melanoma cells via autocrine KIT ligand signalling.
MeSH term(s)	Amino Acid Motifs ; Base Sequence ; Binding Sites ; CD36 Antigens/genetics ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Genes, Neoplasm/genetics ; Genetic Loci/genetics ; Genome, Human/genetics ; Genome-Wide Association Study ; Homeodomain Proteins/chemistry ; Homeodomain Proteins/genetics ; Humans ; Melanoma/genetics ; Melanoma/pathology ; Microphthalmia-Associated Transcription Factor/genetics ; Molecular Sequence Data ; POU Domain Factors/chemistry ; POU Domain Factors/genetics ; Promoter Regions, Genetic ; Protein Binding ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology ; Stem Cell Factor/genetics ; Transcriptional Activation/genetics ; Wnt Proteins/genetics
Chemical Substances	CD36 Antigens ; Homeodomain Proteins ; Microphthalmia-Associated Transcription Factor ; POU Domain Factors ; Stem Cell Factor ; WNT16 protein, human ; Wnt Proteins ; transcription factor Brn-2
Language	English
Publishing date	2010-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2409570-9
ISSN	1755-148X ; 1600-0749 ; 0893-5785 ; 1755-1471
ISSN (online)	1755-148X ; 1600-0749
ISSN	0893-5785 ; 1755-1471
DOI	10.1111/j.1755-148X.2010.00697.x
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Zs.A 2444: Show issues

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Article ; Online: Systematic identification of signal integration by protein kinase A.

Filteau, Marie / Diss, Guillaume / Torres-Quiroz, Francisco / Dubé, Alexandre K / Schraffl, Andrea / Bachmann, Verena A / Gagnon-Arsenault, Isabelle / Chrétien, Andrée-Ève / Steunou, Anne-Lise / Dionne, Ugo / Côté, Jacques / Bisson, Nicolas / Stefan, Eduard / Landry, Christian R

Proceedings of the National Academy of Sciences of the United States of America

2015 Volume 112, Issue 14, Page(s) 4501–4506

Abstract: Cellular processes and homeostasis control in eukaryotic cells is achieved by the action of regulatory proteins such as protein kinase A (PKA). Although the outbound signals from PKA directed to processes such as metabolism, growth, and aging have been ... ...

Abstract	Cellular processes and homeostasis control in eukaryotic cells is achieved by the action of regulatory proteins such as protein kinase A (PKA). Although the outbound signals from PKA directed to processes such as metabolism, growth, and aging have been well charted, what regulates this conserved regulator remains to be systematically identified to understand how it coordinates biological processes. Using a yeast PKA reporter assay, we identified genes that influence PKA activity by measuring protein-protein interactions between the regulatory and the two catalytic subunits of the PKA complex in 3,726 yeast genetic-deletion backgrounds grown on two carbon sources. Overall, nearly 500 genes were found to be connected directly or indirectly to PKA regulation, including 80 core regulators, denoting a wide diversity of signals regulating PKA, within and beyond the described upstream linear pathways. PKA regulators span multiple processes, including the antagonistic autophagy and methionine biosynthesis pathways. Our results converge toward mechanisms of PKA posttranslational regulation by lysine acetylation, which is conserved between yeast and humans and that, we show, regulates protein complex formation in mammals and carbohydrate storage and aging in yeast. Taken together, these results show that the extent of PKA input matches with its output, because this kinase receives information from upstream and downstream processes, and highlight how biological processes are interconnected and coordinated by PKA.
MeSH term(s)	Acetylation ; Amino Acid Sequence ; Animals ; Autophagy ; Cyclic AMP/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Galactose/chemistry ; Glucose/chemistry ; HEK293 Cells ; Homeostasis ; Humans ; Luciferases, Renilla/metabolism ; Methionine/chemistry ; Molecular Sequence Data ; Phylogeny ; Protein Processing, Post-Translational ; Rats ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Sequence Homology, Amino Acid ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Saccharomyces cerevisiae Proteins ; Methionine (AE28F7PNPL) ; Cyclic AMP (E0399OZS9N) ; Luciferases, Renilla (EC 1.13.12.5) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Glucose (IY9XDZ35W2) ; Galactose (X2RN3Q8DNE)
Language	English
Publishing date	2015-03-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1409938112
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Article ; Online: mChIP-KAT-MS, a method to map protein interactions and acetylation sites for lysine acetyltransferases.

Mitchell, Leslie / Huard, Sylvain / Cotrut, Michael / Pourhanifeh-Lemeri, Roghayeh / Steunou, Anne-Lise / Hamza, Akil / Lambert, Jean-Philippe / Zhou, Hu / Ning, Zhibin / Basu, Amrita / Côté, Jacques / Figeys, Daniel A / Baetz, Kristin

Proceedings of the National Academy of Sciences of the United States of America

2013 Volume 110, Issue 17, Page(s) E1641–50

Abstract: Recent global proteomic and genomic studies have determined that lysine acetylation is a highly abundant posttranslational modification. The next challenge is connecting lysine acetyltransferases (KATs) to their cellular targets. We hypothesize that ... ...

Abstract	Recent global proteomic and genomic studies have determined that lysine acetylation is a highly abundant posttranslational modification. The next challenge is connecting lysine acetyltransferases (KATs) to their cellular targets. We hypothesize that proteins that physically interact with KATs may not only predict the cellular function of the KATs but may be acetylation targets. We have developed a mass spectrometry-based method that generates a KAT protein interaction network from which we simultaneously identify both in vivo acetylation sites and in vitro acetylation sites. This modified chromatin-immunopurification coupled to an in vitro KAT assay with mass spectrometry (mChIP-KAT-MS) was applied to the Saccharomyces cerevisiae KAT nucleosome acetyltransferase of histone H4 (NuA4). Using mChIP-KAT-MS, we define the NuA4 interactome and in vitro-enriched acetylome, identifying over 70 previously undescribed physical interaction partners for the complex and over 150 acetyl lysine residues, of which 108 are NuA4-specific in vitro sites. Through this method we determine NuA4 acetylation of its own subunit Epl1 is a means of self-regulation and identify a unique link between NuA4 and the spindle pole body. Our work demonstrates that this methodology may serve as a valuable tool in connecting KATs with their cellular targets.
MeSH term(s)	Acetylation ; Chromatin Immunoprecipitation/methods ; Histone Acetyltransferases/metabolism ; Lysine/metabolism ; Mass Spectrometry/methods ; Protein Interaction Mapping/methods ; Protein Processing, Post-Translational/physiology ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/metabolism ; Substrate Specificity
Chemical Substances	Saccharomyces cerevisiae Proteins ; Histone Acetyltransferases (EC 2.3.1.48) ; NuA4 protein, S cerevisiae (EC 2.3.1.48) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2013-04-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Validation Study
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1218515110
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Article ; Online: Phosphorylation of BRN2 modulates its interaction with the Pax3 promoter to control melanocyte migration and proliferation.

Berlin, Irina / Denat, Laurence / Steunou, Anne-Lise / Puig, Isabel / Champeval, Delphine / Colombo, Sophie / Roberts, Karen / Bonvin, Elise / Bourgeois, Yveline / Davidson, Irwin / Delmas, Véronique / Nieto, Laurence / Goding, Colin R / Larue, Lionel

Molecular and cellular biology

2012 Volume 32, Issue 7, Page(s) 1237–1247

Abstract: MITF-M and PAX3 are proteins central to the establishment and transformation of the melanocyte lineage. They control various cellular mechanisms, including migration and proliferation. BRN2 is a POU domain transcription factor expressed in melanoma cell ... ...

Abstract	MITF-M and PAX3 are proteins central to the establishment and transformation of the melanocyte lineage. They control various cellular mechanisms, including migration and proliferation. BRN2 is a POU domain transcription factor expressed in melanoma cell lines and is involved in proliferation and invasion, at least in part by regulating the expression of MITF-M and PAX3. The T361 and S362 residues of BRN2, both in the POU domain, are conserved throughout the POU protein family and are targets for phosphorylation, but their roles in vivo remain unknown. To examine the role of this phosphorylation, we generated mutant BRN2 in which these two residues were replaced with alanines (BRN2TS→BRN2AA). When expressed in melanocytes in vitro or in the melanocyte lineage in transgenic mice, BRN2TS induced proliferation and repressed migration, whereas BRN2AA repressed both proliferation and migration. BRN2TS and BRN2AA bound and repressed the MITF-M promoter, whereas PAX3 transcription was induced by BRN2TS but repressed by BRN2AA. Expression of the BRN2AA transgene in a Mitf heterozygous background and in a Pax3 mutant background enhanced the coat color phenotype. Our findings show that melanocyte migration and proliferation are controlled both through the regulation of PAX3 by nonphosphorylated BRN2 and through the regulation of MITF-M by the overall BRN2 level.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Humans ; Melanocytes/cytology ; Melanocytes/metabolism ; Melanoma/genetics ; Melanoma/metabolism ; Mice ; Mice, Transgenic ; Microphthalmia-Associated Transcription Factor/genetics ; Mutation ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; PAX3 Transcription Factor ; POU Domain Factors/genetics ; POU Domain Factors/metabolism ; Paired Box Transcription Factors/genetics ; Phenotype ; Phosphorylation ; Promoter Regions, Genetic ; Transcription, Genetic
Chemical Substances	Microphthalmia-Associated Transcription Factor ; Mitf protein, mouse ; Nerve Tissue Proteins ; PAX3 Transcription Factor ; POU Domain Factors ; Paired Box Transcription Factors ; Pax3 protein, mouse (138016-91-8) ; Pou3f2 protein, mouse (147258-11-5)
Language	English
Publishing date	2012-01-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.06257-11
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Article ; Online: Identification of the hypoxia-inducible factor 2α nuclear interactome in melanoma cells reveals master proteins involved in melanoma development.

Steunou, Anne-Lise / Ducoux-Petit, Manuelle / Lazar, Ikrame / Monsarrat, Bernard / Erard, Monique / Muller, Catherine / Clottes, Eric / Burlet-Schiltz, Odile / Nieto, Laurence

Molecular & cellular proteomics : MCP

2012 Volume 12, Issue 3, Page(s) 736–748

Abstract: Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors that play a key role in cellular adaptation to hypoxia. HIF proteins are composed of an α subunit regulated by oxygen pressure (essentially HIF1α or HIF2α) and a constitutively ... ...

Abstract	Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors that play a key role in cellular adaptation to hypoxia. HIF proteins are composed of an α subunit regulated by oxygen pressure (essentially HIF1α or HIF2α) and a constitutively expressed β subunit. These proteins are often overexpressed in cancer cells, and HIF overexpression frequently correlates with poor prognosis, making HIF proteins promising therapeutic targets. HIF proteins are involved in melanoma initiation and progression; however, the specific function of HIF2 in melanoma has not yet been studied comprehensively. Identifying protein complexes is a valuable way to uncover protein function, and affinity purification coupled with mass spectrometry and label-free quantification is a reliable method for this approach. We therefore applied quantitative interaction proteomics to identify exhaustively the nuclear complexes containing HIF2α in a human melanoma cell line, 501mel. We report, for the first time, a high-throughput analysis of the interactome of an HIF subunit. Seventy proteins were identified that interact with HIF2α, including some well-known HIF partners and some new interactors. The new HIF2α partners microphthalmia-associated transcription factor, SOX10, and AP2α, which are master actors of melanoma development, were confirmed via co-immunoprecipitation experiments. Their ability to bind to HIF1α was also tested: microphthalmia-associated transcription factor and SOX10 were confirmed as HIF1α partners, but the transcription factor AP2α was not. AP2α expression correlates with low invasive capacities. Interestingly, we demonstrated that when HIF2α was overexpressed, only cells expressing large amounts of AP2α exhibited decreased invasive capacities in hypoxia relative to normoxia. The simultaneous presence of both transcription factors therefore reduces cells' invasive properties. Knowledge of the HIF2α interactome is thus a useful resource for investigating the general mechanisms of HIF function and regulation, and here we reveal unexpected, distinct roles for the HIF1 and HIF2 isoforms in melanoma progression.
MeSH term(s)	Amino Acid Sequence ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Blotting, Western ; Cell Hypoxia ; Cell Line, Tumor ; Cell Movement ; Cell Nucleus/metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Immunoprecipitation ; Mass Spectrometry/methods ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Microphthalmia-Associated Transcription Factor/genetics ; Microphthalmia-Associated Transcription Factor/metabolism ; Models, Biological ; Molecular Sequence Data ; Protein Binding ; Protein Interaction Mapping/methods ; Proteome/genetics ; Proteome/metabolism ; Proteomics/methods ; RNA Interference ; SOXE Transcription Factors/genetics ; SOXE Transcription Factors/metabolism ; Sequence Homology, Amino Acid ; Transcription Factor AP-2/genetics ; Transcription Factor AP-2/metabolism
Chemical Substances	Basic Helix-Loop-Helix Transcription Factors ; HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; MITF protein, human ; Microphthalmia-Associated Transcription Factor ; Proteome ; SOX10 protein, human ; SOXE Transcription Factors ; TFAP2A protein, human ; Transcription Factor AP-2 ; endothelial PAS domain-containing protein 1 (1B37H0967P)
Language	English
Publishing date	2012-12-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
DOI	10.1074/mcp.M112.020727
Database	MEDical Literature Analysis and Retrieval System OnLINE

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