Direct association between PU.1 and MeCP2 that recruits mSin3A-HDAC complex for PU.1-mediated transcriptional repression
Abstract
PU.1, a member of the Ets family of transcription factors, is implicated in hematopoietic cell differentiation through its interactions with other transcriptional factors and cofactors. To identify a novel protein(s) binding to PU.1, we carried out affinity purification using a column of Glutathione-Sepharose beads bound to GST-PU.1 fusion protein and isolated several individual proteins using murine erythroleukemia (MEL) cell extracts. Sequence analysis of these proteins revealed that one was MeCP2 a methyl CpG binding protein. GST-pull-down assay and immunoprecipitation assay showed that PU.1 bound directly to MeCP2 via its Ets domain and MeCP2 bound to PU.1 via either its amino terminal domain or trans-repression domain. MeCP2 repressed transcriptional activity of PU.1 on a reporter construct with trimerized PU.1 binding sites. This downregulation was recovered in the presence of histone deacetylase inhibitor, trichostatin A (TSA). MeCP2 was integrated in PU.1-mSin3A-HDAC complex but not in PU.1-CBP complex. Chromatin immunoprecipitation (ChIP) assays showed that PU.1 and MeCP2 were collocated at the PU.1 binding site on the reporter construct and the PU.1 binding site of the intervening sequence 2 (IVS2) region in the intron of the beta-globin gene, which has been proposed to regulate expression of the gene, in undifferentiated MEL cells. The complex disappeared from the region during the course of erythroid differentiation of MEL cells. Our results suggest that MeCP2 acts as a corepressor of PU.1 probably due to facilitating complex formation with mSin3A and HDACs.
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Association between PU.1 and this repressive complex has previously been suggested to represent an endogenous defense mechanism in erythroid cells that restricts leukemia-associated gene expression and survival.
“Association between PU.1 and this repressive complex has previously been suggested to represent an endogenous defense mechanism in erythroid cells that restricts leukemia-associated gene expression and survival (Gregoricchio et al., 2022; Suzuki et al., 2003).”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Suzuki et al., 2003
There is limited understanding of the mechanisms that determine coactivator versus corepressor recruitment by RUNX1 and PU.1.
“There is limited understanding of the mechanisms that determine coactivator versus corepressor recruitment by RUNX1 and PU.1.17–20”
From RUNX1 regulates corepressor interactions of PU.1 (2011) · cites this paper as [17]
PU.1 can interact with coactivators or corepressors to function as either a transcriptional activator or a transcriptional repressor.
“PU.1 can interact with coactivators or corepressors to function as either a transcriptional activator or a transcriptional repressor.17–19”
From RUNX1 regulates corepressor interactions of PU.1 (2011) · cites this paper as [17]
The mechanisms that regulate corepressor versus coactivator interactions of RUNX1 and PU.1 are incompletely understood.
“However, the mechanisms that regulate corepressor versus coactivator interactions of RUNX1 and PU.1 are incompletely understood.17–20”
From RUNX1 regulates corepressor interactions of PU.1 (2011) · cites this paper as [17]
PU.1 is a transcription repressor that interacts with the Il10 promoter.
“PU.1 is a transcription repressor that interacts with the Il10 promoter27,28.”
From The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance (2009) · cites this paper as [28]
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Loss of HDAC11 ameliorates clinical symptoms in a multiple sclerosis mouse model
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PU.1 Suppresses Th2 Cytokine Expression via Silencing of GATA3 Transcription in Dendritic Cells
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Macrophage‐targeted delivery of siRNA to silence Mecp2 gene expression attenuates pulmonary fibrosis
Mou, Y., Wu, G., Wang, Q., Pan, T. S., Zhang, L., Xu, Y., Xiong, W., Zhou, Q., & Wang, Y. (2021) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10280 · Cited by 38 · see citing works
“1.(24) As a critical transcription factor for M2 macrophage polarization,(35) Pu.”
BackgroundNakazawa, Y., Suzuki, M., Manabe, N., Yamada, T., Kihara‐Negishi, F., Sakurai, T., Tenen, D. G., Iwama, A., Mochizuki, M., & Oikawa, T. (2007) · Oncogene · doi:10.1038/sj.onc.1210140 · Cited by 39 · see citing works
“ChIP assays were performed as reported previously (Suzuki et al., 2003).”
BackgroundMethodInfluentialSelf-citationEpigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia
Ridinger-Saison, M., Evanno, E., Gallais, I., Rimmelé, P., Selimoglu-Buet, D., Sapharikas, E., Moreau-Gachelin, F., & Guillouf, C. (2013) · Cell Death & Differentiation · doi:10.1038/cdd.2013.88 · Cited by 34 · see citing works
“Other studies reported that Spi-1 represses gene transcription by epigenetic mechanisms involving the formation of repressive H3K9 trimethylation(44) and the recruitment of histone deacetylases.(45) Recent data also identified Spi-1 binding to enhancers as a primary event that facilitates H3K4me1 deposition.”
BackgroundA novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation
Ralvenius, W. T., Mungenast, A. E., Woolf, H., Huston, M. M., Gillingham, T. Z., Godin, S. K., Penney, J., Cam, H. P., Gao, F., Fernandez, C. G., et al. (2023) · Journal of Experimental Medicine · doi:10.1084/jem.20222105 · Cited by 31 · see citing works
“Association between PU.1 and this repressive complex has previously been suggested to represent an endogenous defense mechanism in erythroid cells that restricts leukemia-associated gene expression and survival (Gregoricchio et al., 2022; Suzuki et al., 2003).”
Cannon, M. E., Currin, K. W., Young, K. L., Perrin, H. J., Vadlamudi, S., Safi, A., Song, L., Wu, Y., Wabitsch, M., Laakso, M., et al. (2019) · G3 Genes Genomes Genetics · doi:10.1534/g3.119.400294 · Cited by 32 · see citing works
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Aberrant epigenetic landscape in intellectual disability
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Hansen, J. C., Wexler, B. B., Rogers, D. J., Hite, K. C., Panchenko, T., Ajith, S., & Black, B. E. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.234609 · Cited by 29 · see citing works
Metallothionein-1 Isoforms and Vimentin Are Direct PU.1 Downstream Target Genes in Leukemia Cells
Imoto, A., Okada, M., Okazaki, T., Kitasato, H., Harigae, H., & Takahashi, S. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.095810 · Cited by 28 · see citing works
Ski can negatively regulates macrophage differentiation through its interaction with PU.1
Ueki, N., Zhang, L., & Haymann, M. J. (2007) · Oncogene · doi:10.1038/sj.onc.1210654 · Cited by 26 · see citing works
“Recently, Suzuki et al. (2003) reported that MeCP2mediated transcriptional repression of PU.1 involves Sin3A and HDAC1 in a TSA-sensitive manner.”
BackgroundNakazaki, E., Tsolmon, S., Han, J., & Isoda, H. (2011) · European Journal of Nutrition · doi:10.1007/s00394-011-0282-4 · Cited by 24 · see citing works
Extending MeCP2 interactome: canonical nucleosomal histones interact with MeCP2
Ortega-Alarcón, D., Claveria‐Gimeno, R., Vega, S., Kalani, L., Jorge-Torres, O. C., Esteller, M., Ausió, J., Abián, O., & Velázquez‐Campoy, A. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae051 · Cited by 22 · see citing works
“…comprises dsDNA (and other nucleic acids, such as ssDNA and ssRNA), and many proteins: ATRX ( 33 ), histone H3 lysine 9 methyltransferase activity ( 34 ), c-Ski ( 35 ), DNMT1 ( 36 ), CoRest ( 37 ), LANA ( 38 ), PU1 ( 39 ), splicing factors ( 40 ), Y box-binding protein 1 ( 41 ) and Brm ( 42 ).”
Uchiumi, F., Sakakibara, G., Sato, J., & Tanuma, S. (2008) · Genes to Cells · doi:10.1111/j.1365-2443.2008.01240.x · Cited by 21 · see citing works
“In contrast, PU.1 could work as a negative transcription regulator (Lloberas et al. 1997; Harendza et al. 2000; Suzuki et al. 2003).”
BackgroundThe Molecular Pathology of Rett Syndrome: Synopsis and Update
Akbarian, S., Jiang, Y. P., & Laforet, G. A. (2006) · NeuroMolecular Medicine · doi:10.1385/nmm:8:4:485 · Cited by 21 · see citing works
“1 (Suzuki et al., 2003), YB-1 (TRD and surrounding regions,”
PU.1 Regulates Positive Regulatory Domain I-Binding Factor 1/Blimp-1 Transcription in Lymphoma Cells
Desai, S., Bolick, S. C. E., Maurin, M. M., & Wright, K. L. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0901120 · Cited by 21 · see citing works
“1 is bifunctional and can either increase or repress transcription of its target promoters (39, 45).”
The role of methyl-CpG binding protein 2 in liver fibrosis
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Histone Deacetylases Function in the Control of Early Hematopoiesis and Erythropoiesis
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Functional assessment of MeCP2 in Rett syndrome and cancers of breast, colon, and prostate
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“MeCP2, MBD1 and MBD2 may also induce hMLH1 silencing by actively recruiting HDAC to the promoter region [17–19].”
BackgroundSodium butyrate modifies the stabilizing complexes of tyrosine hydroxylase mRNA
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Kihara-Negishi, F., Suzuki, M., Yamada, T., Sakurai, T., & Oikawa, T. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.07.098 · Cited by 13 · see citing works
Self-citationHuman microglial cells as a therapeutic target in a neurodevelopmental disease model
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Identification of Novel MeCP2 Cancer-Associated Target Genes and Post-Translational Modifications
Castro‐Piedras, I., Vartak, D., Sharma, M., Pandey, S., Casas, L., Molehin, D., Rasha, F. A., Fokar, M., Nichols, J., Almodóvar, S., et al. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.576362 · Cited by 12 · see citing works
“Additionally, MeCP2 regulates tumor suppressor genes (TSG) silencing, and serves as a critical bridge for histone methyltransferases (HMTs) (25), histone deacetylases (HDACs) (26, 28, 39), and other proteins that bind modified histones or that mediate nucleosome remodeling (27, 40, 41).”
BackgroundYamada, T., Shimizu, T., Suzuki, M., Kihara‐Negishi, F., Nanashima, N., Sakurai, T., Yang, F., Akita, M., Oikawa, T., & Tsuchida, S. (2007) · Experimental Cell Research · doi:10.1016/j.yexcr.2007.11.005 · Cited by 11 · see citing works
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“Such structural organization facilitates MBD-dependent binding to methylated DNA and is essential for interaction with transcriptional repressor mSin3A [316], nuclear receptor corepressor (NCoR) [317], Ski [318], putative Xenopus protease p20 [319], and DNA methyltransferase DNMT1 [320].”
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Extensive remodeling of DC function by rapid maturation-induced transcriptional silencing
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“1 has been attributed to its ability to recruit HDACs (40,41), a mechanism consistent with the finding that histone-deacetylation is the primary event associated with the silencing process we have unveiled.”
BackgroundMi2β Shows Chromatin Enzyme Specificity by Erasing a DNase I-hypersensitive Site Established by ACF
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“Coimmunoprecipitation studies showed that MeCP2 interacts with histone deacetylases and Sin3a through its transcriptional repressor domain, and this helped establish its role as a transcriptional repressor, through its ability to recruit the aforementioned interacting partners (Jones et al. 1998; Nan et al. 1998; Suzu…”
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Qualitative Determination of 5-Methylcytosine and Other Components of the DNA Methylation Machinery
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“…[90,91]; disrupting the stability and function of G-quadruplex structures, potentially compromising their role in regulating gene expression [51]; and, inhibiting the binding of MeCP2, a DNA methylation “ reader ” , which can recruit histone deacetylases to alter chromatin conformation [92 – 94].”
PU.1, a Versatile Transcription Factor and a Suppressor of Myeloid Leukemia
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“(Suzuki et al., 2003) found that PU.”
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Regulation of positive regulatory domain I-binding factor 1 and its role in mantle cell lymphoma
Desai, S. (2010) · Digital Commons - University of South Florida (University of South Florida)
Global analysis of the methyl-CpG binding protein MeCP2
Skene, P. J. (2010) · ERA
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The Transcription Factor ERG is a Gatekeeper of Endothelial Cell Homeostasis
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Old dog PU.1 reveals new tricks
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Lung Defects Contribute to Respiratory Symptoms in a Mecp2-mutant Mouse Model of Rett Syndrome
Vashi, N. (2021) · TSpace (University of Toronto)
Identification and Characterization of Novel Sir3/MeCP2-Chromatin Interactions
Adkins, N. L. (2009)
Chatagnon, A. (2009) · doi:10.70675/961a765bz6db3z4b84zb18fz9f5730f0bb83
“De la même façon, une association entre le facteur de transcription PU.1, MeCP2 et le complexe mSin3A-HDAC sur le gène de la -globine a été démontré par Suzuki et al. (Suzuki et al., 2003).”
BackgroundMeCP2 functions as a DNA methylation reader in immune homeostasis and cancer
Stroman, G. C., Mellows, C., & Pruitt, K. (2026) · Frontiers in Epigenetics and Epigenomics · doi:10.3389/freae.2026.1917394
- Authors
- Suzuki, M., Yamada, T., Kihara-Negishi, F., Sakurai, T., & Oikawa, T.
- Affiliations
- Sasaki Institute (JP)
- Corresponding author
- Oikawa, Tsuneyuki
- Venue
- Oncogene
- Published
- 2003-11-27
- Volume
- 22
- Issue
- 54
- Pages
- 8688-8698
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2019393914
- Cited by
- 82
- References
- 43
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 5 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 4 · 2014: 3 · 2013: 4 · 2012: 4
- FWCI
- 1.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- PU.1, MeCP2, mSin3A, histone deacetylase, transcriptional repression, corepressors, ETS transcription factors, methyl-CpG binding proteins
- MeSH terms
- Proto-Oncogene Protein Spi-1, Cell Differentiation, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins, Leukemia, Erythroblastic, Acute, Histone Deacetylases
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