Relationship between the structure and function of the transcriptional regulator E2A

AbstractE proteins are transcriptional regulators that regulate many developmental processes in animals and lymphocytosis and leukemia in Homo sapiens. In particular, E2A, a member of the E protein family, plays a major role in the transcriptional regulatory network that promotes the differentiation and development of B and T lymphocytes. E2A-mediated transcriptional regulation usually requires the formation of E2A dimers, which then bind to coregulators. In this review, we summarize the mechanisms by which E2A participates in transcriptional regulation from a structural perspective. More specifically, the C-terminal helix-loop-helix (HLH) region of the basic HLH (bHLH) domain first dimerizes, and then the activation domains of E2A bind to different coactivators or corepressors in different cell contexts, resulting in histone acetylation or deacetylation, respectively. Then, the N-terminal basic region (b) of the bHLH domain binds to or dissociates from a specific DNA motif (E-box sequence). Last, trans-activation or trans-repression occurs. We also summarize the properties of these E2A domains and their interactions with the domains of other proteins. The feasibility of developing drugs based on these domains is discussed.

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

Molecular and Cellular Biology ◽

10.1128/mcb.00073-09 ◽

2009 ◽

Vol 29 (10) ◽

pp. 2644-2657 ◽

Cited By ~ 23

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.

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Functions of the podocyte proteins nephrin and Neph3 and the transcriptional regulation of their genes

Clinical Science ◽

10.1042/cs20130258 ◽

2013 ◽

Vol 126 (5) ◽

pp. 315-328 ◽

Cited By ~ 24

Author(s):

Mervi Ristola ◽

Sanna Lehtonen

Keyword(s):

Transcriptional Regulation ◽

Cell Adhesion ◽

Current Knowledge ◽

Immunoglobulin Superfamily ◽

Transcriptional Regulatory ◽

Glomerular Ultrafiltration ◽

Transcriptional Regulatory Mechanisms ◽

Podocyte Proteins ◽

And Function ◽

Bidirectional Gene Pair

Nephrin and Neph-family proteins [Neph1–3 (nephrin-like 1–3)] belong to the immunoglobulin superfamily of cell-adhesion receptors and are expressed in the glomerular podocytes. Both nephrin and Neph-family members function in cell adhesion and signalling, and thus regulate the structure and function of podocytes and maintain normal glomerular ultrafiltration. The expression of nephrin and Neph3 is altered in human proteinuric diseases emphasizing the importance of studying the transcriptional regulation of the nephrin and Neph3 genes NPHS1 (nephrosis 1, congenital, Finnish type) and KIRREL2 (kin of IRRE-like 2) respectively. The nephrin and Neph3 genes form a bidirectional gene pair, and they share transcriptional regulatory mechanisms. In the present review, we summarize the current knowledge of the functions of nephrin and Neph-family proteins and transcription factors and agents that control nephrin and Neph3 gene expression.

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Identification and characterization of jasmonic acid- and linolenic acid-mediated transcriptional regulation of secondary laticifer differentiation in Hevea brasiliensis

Scientific Reports ◽

10.1038/s41598-019-50800-1 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Swee Cheng Loh ◽

Ahmad Sofiman Othman ◽

G. Veera Singham

Keyword(s):

Jasmonic Acid ◽

Linolenic Acid ◽

Hevea Brasiliensis ◽

Transcriptional Regulatory Network ◽

Gene Families ◽

Differentially Expressed ◽

Ethylene Response Factor ◽

Rna Seq ◽

Helix Loop Helix ◽

Transcriptional Regulatory

Abstract Hevea brasiliensis remains the primary crop commercially exploited to obtain latex, which is produced from the articulated secondary laticifer. Here, we described the transcriptional events related to jasmonic acid (JA)- and linolenic acid (LA)-induced secondary laticifer differentiation (SLD) in H. brasiliensis clone RRIM 600 based on RNA-seq approach. Histochemical approach proved that JA- and LA-treated samples resulted in SLD in H. brasiliensis when compared to ethephon and untreated control. RNA-seq data resulted in 86,614 unigenes, of which 2,664 genes were differentially expressed in JA and LA-induced secondary laticifer harvested from H. brasiliensis bark samples. Among these, 450 genes were unique to JA and LA as they were not differentially expressed in ethephon-treated samples compared with the untreated samples. Most transcription factors from the JA- and LA-specific dataset were classified under MYB, APETALA2/ethylene response factor (AP2/ERF), and basic-helix-loop-helix (bHLH) gene families that were involved in tissue developmental pathways, and we proposed that Bel5-GA2 oxidase 1-KNOTTED-like homeobox complex are likely involved in JA- and LA-induced SLD in H. brasiliensis. We also discovered alternative spliced transcripts, putative novel transcripts, and cis-natural antisense transcript pairs related to SLD event. This study has advanced understanding on the transcriptional regulatory network of SLD in H. brasiliensis.

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Transcriptional Regulatory Network for the Development of Innate Lymphoid Cells

Mediators of Inflammation ◽

10.1155/2015/264502 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Chao Zhong ◽

Jinfang Zhu

Keyword(s):

Transcription Factors ◽

Regulatory Network ◽

Transcriptional Regulatory Network ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

T Helper ◽

Th Cells ◽

Transcriptional Regulatory ◽

Effector Cytokines ◽

And Function

Recent studies on innate lymphoid cells (ILCs) have expanded our knowledge about the innate arm of the immune system. Helper-like ILCs share both the “innate” feature of conventional natural killer (cNK) cells and the “helper” feature of CD4+T helper (Th) cells. With this combination, helper-like ILCs are capable of initiating early immune responses similar to cNK cells, but via secretion of a set of effector cytokines similar to those produced by Th cells. Although many studies have revealed the functional similarity between helper-like ILCs and Th cells, some aspects of ILCs including the development of this lineage remain elusive. It is intriguing that the majority of transcription factors involved in multiple stages of T cell development, differentiation, and function also play critical roles during ILC development. Regulators such as Id2, GATA-3, Nfil3, TOX, and TCF-1 are expressed and function at various stages of ILC development. In this review, we will summarize the expression and functions of these transcription factors shared by ILCs and Th cells. We will also propose a complex transcriptional regulatory network for the lineage commitment of ILCs.

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Molecular Mechanisms and Potential Treatment Targets for Ovarian Cancer by Analyzing Transcriptional Regulatory Network

Letters in Drug Design & Discovery ◽

10.2174/1570180813666160920122412 ◽

2016 ◽

Vol 14 (1) ◽

pp. 112-118

Author(s):

Fei Wu ◽

Xinrui Liu ◽

Yujie Sui ◽

Tianmin Xu ◽

Manhua Cui

Keyword(s):

Ovarian Cancer ◽

Regulatory Network ◽

Molecular Mechanisms ◽

Transcriptional Regulatory Network ◽

Potential Treatment ◽

Treatment Targets ◽

Transcriptional Regulatory

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Mathematical Model of a Telomerase Transcriptional Regulatory Network Developed by Cell-Based Screening: Analysis of Inhibitor Effects and Telomerase Expression Mechanisms

PLoS Computational Biology ◽

10.1371/journal.pcbi.1003448 ◽

2014 ◽

Vol 10 (2) ◽

pp. e1003448 ◽

Cited By ~ 11

Author(s):

Alan E. Bilsland ◽

Katrina Stevenson ◽

Yu Liu ◽

Stacey Hoare ◽

Claire J. Cairney ◽

...

Keyword(s):

Mathematical Model ◽

Regulatory Network ◽

Transcriptional Regulatory Network ◽

Screening Analysis ◽

Transcriptional Regulatory

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Antibiotic tolerance is associated with a broad and complex transcriptional response in E. coli

Scientific Reports ◽

10.1038/s41598-021-85509-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Heather S. Deter ◽

Tahmina Hossain ◽

Nicholas C. Butzin

Keyword(s):

Transcriptional Regulatory Network ◽

Transcriptional Response ◽

Regulatory Proteins ◽

Health Concern ◽

Transcriptional Networks ◽

Antibiotic Tolerance ◽

Multiple Gene ◽

E Coli ◽

Transcriptional Regulatory ◽

Antibiotic Efficacy

AbstractAntibiotic treatment kills a large portion of a population, while a small, tolerant subpopulation survives. Tolerant bacteria disrupt antibiotic efficacy and increase the likelihood that a population gains antibiotic resistance, a growing health concern. We examined how E. coli transcriptional networks changed in response to lethal ampicillin concentrations. We are the first to apply transcriptional regulatory network (TRN) analysis to antibiotic tolerance by leveraging existing knowledge and our transcriptional data. TRN analysis shows that gene expression changes specific to ampicillin treatment are likely caused by specific sigma and transcription factors typically regulated by proteolysis. These results demonstrate that to survive lethal concentration of ampicillin specific regulatory proteins change activity and cause a coordinated transcriptional response that leverages multiple gene systems.

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Genetic program activity delineates risk, relapse, and therapy responsiveness in multiple myeloma

npj Precision Oncology ◽

10.1038/s41698-021-00185-0 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Matthew A. Wall ◽

Serdar Turkarslan ◽

Wei-Ju Wu ◽

Samuel A. Danziger ◽

David J. Reiss ◽

...

Keyword(s):

Multiple Myeloma ◽

Chromosomal Abnormalities ◽

Transcriptional Regulatory Network ◽

Progression Free Survival ◽

Cross Sectional ◽

Free Survival ◽

Extreme Risk ◽

Transcriptional Regulatory ◽

Transcription Regulators ◽

Immunosuppressive Microenvironment

AbstractDespite recent advancements in the treatment of multiple myeloma (MM), nearly all patients ultimately relapse and many become refractory to multiple lines of therapies. Therefore, we not only need the ability to predict which patients are at high risk for disease progression but also a means to understand the mechanisms underlying their risk. Here, we report a transcriptional regulatory network (TRN) for MM inferred from cross-sectional multi-omics data from 881 patients that predicts how 124 chromosomal abnormalities and somatic mutations causally perturb 392 transcription regulators of 8549 genes to manifest in distinct clinical phenotypes and outcomes. We identified 141 genetic programs whose activity profiles stratify patients into 25 distinct transcriptional states and proved to be more predictive of outcomes than did mutations. The coherence of these programs and accuracy of our network-based risk prediction was validated in two independent datasets. We observed subtype-specific vulnerabilities to interventions with existing drugs and revealed plausible mechanisms for relapse, including the establishment of an immunosuppressive microenvironment. Investigation of the t(4;14) clinical subtype using the TRN revealed that 16% of these patients exhibit an extreme-risk combination of genetic programs (median progression-free survival of 5 months) that create a distinct phenotype with targetable genes and pathways.

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