scholarly journals Multivalent Binding of the ETO Corepressor to E Proteins Facilitates Dual Repression Controls Targeting Chromatin and the Basal Transcription Machinery

2009 ◽  
Vol 29 (10) ◽  
pp. 2644-2657 ◽  
Author(s):  
Chun Guo ◽  
Qiande Hu ◽  
Chunxia Yan ◽  
Jinsong Zhang
Keyword(s):  
Fusion Protein ◽  
Protein Fusion ◽  
Protein Activity ◽  
E Proteins ◽  
Basal Transcription ◽  
Activation Domains ◽  
Basal Transcription Machinery ◽  
Transcription Machinery ◽  
Helix Loop Helix ◽  
E Protein

ABSTRACT E proteins are a family of helix-loop-helix transcription factors that play important roles in cell differentiation and homeostasis. They contain at least two activation domains, AD1 and AD2. ETO family proteins and the leukemogenic AML1-ETO fusion protein are corepressors of E proteins. It is thought that ETO represses E-protein activity by interacting with AD1, which competes away p300/CBP histone acetyltransferases. Here we report that E proteins contain another conserved ETO-interacting region, termed DES, and that differential associations with AD1 and DES allow ETO to repress transcription through both chromatin-dependent and chromatin-independent mechanisms. At the chromatin level, AD1 and AD2 cooperatively recruit p300. ETO interacts with AD1 to abolish p300 recruitment and to allow HDAC-dependent silencing. At the post-chromatin-remodeling level, binding to DES enables ETO to directly inhibit activation of the basal transcription machinery. This novel repression mechanism is conserved in ETO family proteins and in the AML1-ETO fusion protein. In addition, the repression capacity exerted by each mechanism is differentially modulated by cross talk among various ETO domains and the AML1 domain of AML1-ETO. In particular, the oligomerization domain of ETO plays a major role in targeting ETO to the DES region and independently potentiates the TAFH domain-mediated AD1 interaction. The ability to exert repression at different levels not only may allow these corepressors to impose robust inhibition of signal-independent transcription but may also allow a rapid response to signals. In addition, our newly defined domain interactions and their interplays have important implications in effectively targeting both E-protein fusion proteins and AML1-ETO found in cancers.

scholarly journals Early B Cell Factor Promotes B Lymphopoiesis with Reduced Interleukin 7 Responsiveness in the Absence of E2A

2004 ◽  
Vol 199 (12) ◽  
pp. 1689-1700 ◽  
Author(s):  
Christopher S. Seet ◽  
Rachel L. Brumbaugh ◽  
Barbara L. Kee
Keyword(s):  
Transcription Factors ◽  
B Cell ◽  
B Lymphopoiesis ◽  
Protein Activity ◽  
E Proteins ◽  
Helix Loop Helix ◽  
Interleukin 7 ◽  
E Protein ◽  
B Lineage ◽  
Early B Cell Factor

The basic helix-loop-helix transcription factors encoded by the E2A gene function at the apex of a transcriptional hierarchy involving E2A, early B cell factor (EBF), and Pax5, which is essential for B lymphopoiesis. In committed B lineage progenitors, E2A proteins have also been shown to regulate many lineage-associated genes. Herein, we demonstrate that the block in B lymphopoiesis imposed by the absence of E2A can be overcome by expression of EBF, but not Pax5, indicating that EBF is the essential target of E2A required for development of B lineage progenitors. Our data demonstrate that EBF, in synergy with low levels of alternative E2A-related proteins (E proteins), is sufficient to promote expression of most B lineage genes. Remarkably, however, we find that E2A proteins are required for interleukin 7–dependent proliferation due, in part, to a role for E2A in optimal expression of N-myc. Therefore, high levels of E protein activity are essential for the activation of EBF and N-myc, whereas lower levels of E protein activity, in synergy with other B lineage transcription factors, are sufficient for expression of most B lineage genes.

scholarly journals Augmenting E Protein Activity Impairs cDC2 Differentiation at the Pre-cDC Stage

2020 ◽  
Vol 11 ◽  
Author(s):  
Sandra Bajana ◽  
Kevin Thomas ◽  
Constantin Georgescu ◽  
Ying Zhao ◽  
Jonathan D. Wren ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Protein Function ◽  
Loss Of Function ◽  
Protein Activity ◽  
E Proteins ◽  
Aberrant Expression ◽  
Precise Control ◽  
Helix Loop Helix ◽  
Id Proteins ◽  
E Protein

Dendritic cell (DC) specification and differentiation are controlled by a circuit of transcription factors, which regulate the expression of DC effector genes as well as the transcription factors themselves. E proteins are a widely expressed basic helix-loop-helix family of transcription factors whose activity is suppressed by their inhibitors, ID proteins. Loss-of-function studies have demonstrated the essential role of both E and ID proteins in different aspects of DC development. In this study, we employed a gain-of-function approach to illustrate the importance of the temporal control of E protein function in maintaining balanced differentiation of conventional DC (cDC) subsets, cDC1 and cDC2. We expressed an E protein mutant, ET2, which dimerizes with endogenous E proteins to overcome inhibition by ID proteins and activate the transcription of E protein targets. Induction of ET2 expression at the hematopoietic progenitor stage led to a dramatic reduction in cDC2 precursors (pre-cDC2s) with little impact on pre-cDC1s. Consequently, we observed decreased numbers of cDC2s in the spleen and lung, as well as in FLT3L-driven bone marrow-derived DC cultures. Furthermore, in mice bearing ET2, we detected increased expression of the IRF8 transcription factor in cDC2s, in which IRF8 is normally down-regulated and IRF4 up-regulated. This aberrant expression of IRF8 induced by ET2 may contribute to the impairment of cDC2 differentiation. In addition, analyses of the transcriptomes of splenic cDC1s and cDC2s revealed that ET2 expression led to a shift, at least in part, of the transcriptional profile characteristic of cDC2s to that of cDC1. Together, these results suggest that a precise control of E protein activity is crucial for balanced DC differentiation.

scholarly journals The basal transcription machinery as a target for cancer therapy

2014 ◽  
Vol 14 (1) ◽  
pp. 18 ◽  
Author(s):  
Claudia Villicaña ◽  
Grisel Cruz ◽  
Mario Zurita
Keyword(s):  
Cancer Therapy ◽  
Basal Transcription ◽  
Basal Transcription Machinery ◽  
Transcription Machinery

scholarly journals Mtg16-dependent repression of E protein activity is required for early lymphopoiesis

2020 ◽  
Author(s):  
Pankaj Acharya ◽  
Shilpa Sampathi ◽  
David K. Flaherty ◽  
Brittany K. Matlock ◽  
Christopher S. Williams ◽  
...  
Keyword(s):  
Stem Cell ◽  
Germ Line ◽  
Adult Stem Cell ◽  
The Cancer Genome Atlas ◽  
Single Nucleotide Variants ◽  
Protein Activity ◽  
E Proteins ◽  
Cell Functions ◽  
E Protein ◽  
Cancer Genome Atlas

AbstractThe ETO/MTG family of transcriptional co-repressors play a key role in adult stem cell functions in various tissues. These factors are commonly found in complex with E proteins such as E2A, HEB, and Lyl1 as well as PRDM14 and BTB/POZ domain factors. Structural studies identified a region in the first domain of MTGs that is conserved in the Drosophila homologue Nervy (Nervy Homology Domain-1, or NHR1) that is essential for ETO/MTG8 to inhibit E protein-dependent transcription. The Cancer Genome Atlas (TCGA) identified cancer associated single nucleotide variants (SNVs) near the MTG16:E protein contact site. We tested these SNVs using sensitive yeast two-hybrid association assays, which suggested that only P209T significantly affected E protein binding. We then used CRISPR-Cas9 and homology directed DNA repair to insert P209T and a known inactivating mutation, F210A, into NHR1 of Mtg16 in the germ line of mice. These mice developed normally, but in competitive bone marrow transplantation assays, the F210A-containing stem cells failed to contribute to lymphopoiesis, while P209T mutant cells were reduced in mature T cell populations. High content fluorescent activated analytical flow cytometry assays identified a defect in the multi-potent progenitor to common lymphoid progenitor transition during lymphopoiesis. These data indicate that the cancer associated changes are likely benign polymorphisms, and the MTG:E protein association is required for lymphopoiesis, but less important for myelopoiesis and stem cell functions.

scholarly journals Cdc28 kinase activity regulates the basal transcription machinery at a subset of genes

2012 ◽  
Vol 109 (26) ◽  
pp. 10450-10455 ◽  
Author(s):  
P. Chymkowitch ◽  
V. Eldholm ◽  
S. Lorenz ◽  
C. Zimmermann ◽  
J. M. Lindvall ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Basal Transcription ◽  
Basal Transcription Machinery ◽  
Transcription Machinery ◽  
Cdc28 Kinase

scholarly journals Deacetylase Activity Is Required for Recruitment of the Basal Transcription Machinery and Transactivation by STAT5

2003 ◽  
Vol 23 (12) ◽  
pp. 4162-4173 ◽  
Author(s):  
Anne Rascle ◽  
James A. Johnston ◽  
Bruno Amati
Keyword(s):  
Chromatin Remodeling ◽  
Chromatin Immunoprecipitation ◽  
Transcription Initiation ◽  
Cellular Response ◽  
Target Genes ◽  
Trichostatin A ◽  
Basal Transcription ◽  
Basal Transcription Machinery ◽  
Transcription Machinery ◽  
Microarray Analyses

ABSTRACT The signal transducer and activator of transcription STAT5 plays a major role in the cellular response to cytokines, but the mechanism by which it activates transcription remains poorly understood. We show here that deacetylase inhibitors (trichostatin A, suberoylanilide hydroxamic acid, and sodium butyrate) prevent induction of endogenous STAT5 target genes, implying that a deacetylase activity is required for that process. Microarray analyses revealed that this requirement is common to all STAT5 target genes. Using chromatin immunoprecipitation, we show that, following STAT5 DNA binding, deacetylase inhibitors block transcription initiation by preventing recruitment of the basal transcription machinery. This inhibition is not due to effects on histone H3 and H4 acetylation or chromatin remodeling within the promoter region. This novel mechanism of transactivation by STAT5 provides a rationale for the use of deacetylase inhibitors for therapeutic intervention in STAT5-associated cancers.

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