scholarly journals An Overview of the Importance of Conformational Flexibility in Gene Regulation by the Transcription Factors

2009 ◽  
Vol 2009 ◽  
pp. 1-9 ◽  
Author(s):  
Shagufta H. Khan ◽  
Raj Kumar
Keyword(s):  
Gene Regulation ◽  
Transcription Factors ◽  
Target Genes ◽  
Conformational Flexibility ◽  
Structural Basis ◽  
Biological Functions ◽  
Multiprotein Complexes ◽  
Cellular Processes ◽  
Intrinsically Disordered ◽  
Coregulatory Proteins

A number of proteins with intrinsically disordered (ID) regions/domains are reported to be found disproportionately higher in transcription factors. Available evidences suggest that presence of ID region/domain within a transcription factor plays an important role in its biological functions. These ID sequences provide large flexible surfaces that can allow them to make more efficient physical and functional interactions with their target partners. Since transcription factors regulate expression of target genes by interacting with specific coregulatory proteins, these ID regions/domains can be used as a platform for such large macromolecular interactions, and may represent a mechanism for regulation of cellular processes. The precise structural basis for the function of these ID regions/domains of the transcription factors remains to be determined. In the recent years there has been growing evidence suggesting that an induced fit-like process leads to imposition of folded functional structure in these ID domains on which large multiprotein complexes are built. These multiprotein complexes may eventually dictate the final outcome of the gene regulation by the transcription factors.

scholarly journals Dynamic control of gene regulatory logic by seemingly redundant transcription factors

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Zohreh AkhavanAghdam ◽  
Joydeb Sinha ◽  
Omar P Tabbaa ◽  
Nan Hao
Keyword(s):  
Gene Regulation ◽  
Transcription Factors ◽  
Target Genes ◽  
Logic Gate ◽  
Dynamic Control ◽  
Activation Kinetics ◽  
General Stress Response ◽  
Two Factors ◽  
Fast Activation ◽  
Or Gate

Many transcription factors co-express with their homologs to regulate identical target genes, however the advantages of such redundancies remain elusive. Using single-cell imaging and microfluidics, we study the yeast general stress response transcription factor Msn2 and its seemingly redundant homolog Msn4. We find that gene regulation by these two factors is analogous to logic gate systems. Target genes with fast activation kinetics can be fully induced by either factor, behaving as an 'OR' gate. In contrast, target genes with slow activation kinetics behave as an 'AND' gate, requiring distinct contributions from both factors, upon transient stimulation. Furthermore, such genes become an 'OR' gate when the input duration is prolonged, suggesting that the logic gate scheme is not static but rather dependent on the input dynamics. Therefore, Msn2 and Msn4 enable a time-based mode of combinatorial gene regulation that might be applicable to homologous transcription factors in other organisms.

scholarly journals Structural insights into target DNA recognition by R2R3-MYB transcription factors

2019 ◽  
Author(s):  
Baihui Wang ◽  
Qiang Luo ◽  
Yingping Li ◽  
Liufan Yin ◽  
Nana Zhou ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Structural Basis ◽  
Myb Transcription Factors ◽  
Target Dna ◽  
Myb Proteins ◽  
R2r3 Myb ◽  
R2r3 Myb Transcription Factors

Abstract As the largest group of MYB family transcription factors, R2R3-MYB proteins play essential roles during plant growth and development. However, the structural basis underlying how R2R3-MYBs recognize the target DNA remains elusive. Here, we report the crystal structure of Arabidopsis WEREWOLF (WER), an R2R3-MYB protein, in complex with its target DNA. Structural analysis showed that the third α-helices in both the R2 and R3 repeats of WER fit in the major groove of the DNA, specifically recognizing the DNA motif 5′-AACNGC-3′. In combination with mutagenesis, in vitro binding and in vivo luciferase assays, we showed that K55, N106, K109 and N110 are critical for the function of WER. Although L59 of WER is not involved in DNA binding in the structure, ITC analysis suggested that L59 plays an important role in sensing DNA methylation at the fifth position of cytosine (5mC). Like 5mC, methylation at the sixth position of adenine (6mA) in the AAC element also inhibits the interaction between WER and its target DNA. Our study not only unravels the molecular basis of how WER recognizes its target DNA, but also suggests that 5mC and 6mA modifications may block the interaction between R2R3-MYB transcription factors and their target genes.

scholarly journals An allosteric peptide inhibitor of HIF-1α regulates hypoxia-induced retinal neovascularization

2020 ◽  
Vol 117 (45) ◽  
pp. 28297-28306
Author(s):  
Ayumi Usui-Ouchi ◽  
Edith Aguilar ◽  
Salome Murinello ◽  
Mitchell Prins ◽  
Marin L. Gantner ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Protein Interactions ◽  
Target Genes ◽  
Vision Loss ◽  
Intrinsically Disordered Protein ◽  
Retinal Neovascularization ◽  
Negative Regulator ◽  
Hypoxic Response ◽  
Intrinsically Disordered ◽  
Anti Vegf

Retinal neovascularization (NV), a leading cause of vision loss, results from localized hypoxia that stabilizes the hypoxia-inducible transcription factors HIF-1α and HIF-2α, enabling the expression of angiogenic factors and genes required to maintain homeostasis under conditions of oxygen stress. HIF transcriptional activity depends on the interaction between its intrinsically disordered C-terminal domain and the transcriptional coactivators CBP/p300. Much effort is currently directed at disrupting protein–protein interactions between disease-associated transcription factors like HIF and their cellular partners. The intrinsically disordered protein CITED2, a direct product of HIF-mediated transcription, functions as a hypersensitive negative regulator that attenuates the hypoxic response by competing allosterically with HIF-1α for binding to CBP/p300. Here, we show that a peptide fragment of CITED2 is taken up by retinal cells and efficiently regulates pathological angiogenesis in murine models of ischemic retinopathy. Both vaso-obliteration (VO) and NV were significantly inhibited in an oxygen-induced retinopathy (OIR) model following intravitreal injection of the CITED2 peptide. The CITED2 peptide localized to retinal neurons and glia, resulting in decreased expression of HIF target genes. Aflibercept, a commonly used anti-VEGF therapy for retinal neovascular diseases, rescued NV but not VO in OIR. However, a combination of the CITED2 peptide and a reduced dose of aflibercept significantly decreased both NV and VO. In contrast to anti-VEGF agents, the CITED2 peptide can rescue hypoxia-induced retinal NV by modulating the hypoxic response through direct competition with HIF for CBP/p300, suggesting a dual targeting strategy for treatment of ischemic retinal diseases and other neovascular disorders.

scholarly journals Absolute quantification of transcription factors reveals principles of gene regulation in erythropoiesis

2019 ◽  
Author(s):  
Mark A. Gillespie ◽  
Carmen G. Palii ◽  
Daniel Sanchez-Taltavull ◽  
Paul Shannon ◽  
William J.R. Longabaugh ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Cell Fate ◽  
Regulatory Network ◽  
Copy Number ◽  
Absolute Quantification ◽  
Cellular Processes ◽  
Gene Regulatory ◽  
Surprising Discovery

SummaryDynamic cellular processes such as differentiation are driven by changes in the abundances of transcription factors (TFs). Yet, despite years of studies we still do not know the protein copy number of TFs in the nucleus. Here, by determining the absolute abundances of 103 TFs and co-factors during the course of human erythropoiesis, we provide a dynamic and quantitative scale for TFs in the nucleus. Furthermore, we establish the first Gene Regulatory Network of cell fate commitment that integrates temporal protein stoichiometry data with mRNA measurements. The model revealed quantitative imbalances in TFs cross-antagonistic relationships that underlie lineage determination. Finally, we made the surprising discovery that in the nucleus, corepressors are dramatically more abundant than coactivators at the protein, but not at the RNA level, with profound implications for understanding transcriptional regulation. These analyses provide a unique quantitative framework to understand transcriptional regulation of cell differentiation in a dynamic context.

scholarly journals An Activity-based Probe Targeting Non-catalytic, Highly Conserved Amino Acid Residues Within Bromodomains

2018 ◽  
Author(s):  
Melissa D’Ascenzio ◽  
Kathryn Pugh ◽  
Rebecca Konietzny ◽  
Georgina Berridge ◽  
Cynthia Tallant ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Transcription Factors ◽  
Amino Acid ◽  
Cancer Development ◽  
Tyrosine Residue ◽  
Amino Acid Residues ◽  
Entire Family ◽  
Cellular Processes ◽  
Wide Range ◽  
Endogenous Proteins

<b>Bromodomain-containing proteins are epigenetic modulators involved in a wide range of cellular processes, from physiological recruitment of transcription factors to pathological disruption of gene regulation and cancer development. Since the druggability of these acetyl-lysine reader domains was established, efforts were made to develop potent and selective inhibitors across the entire family. Here we report the development of a small molecule based approach to covalently modify recombinant and endogenous bromodomain-containing proteins by targeting a conserved lysine and a tyrosine residue in the variable ZA or BC loops. Moreover, the addition of a reporter tag, via copper-catalyzed alkyne azide coupling, to an alkyne handle on the probe allowed in-gel visualization and selective pull-down of the desired bromodomains using both recombinant and endogenous proteins.</b>

scholarly journals LncRNAOIP5-AS1is overexpressed in undifferentiated oral tumors and integrated analysis identifies as a downstream effector of stemness-associated transcription factors

2018 ◽  
Author(s):  
Ganesan Arunkumar ◽  
Shankar Anand ◽  
Partha Raksha ◽  
Shankar Dhamodharan ◽  
Harikrishnan Prasanna Srinivasa Rao ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Binding Site ◽  
Target Genes ◽  
Integrated Analysis ◽  
Downstream Target ◽  
Cellular Processes ◽  
Downstream Effector ◽  
Undifferentiated Tumors ◽  
Oral Tumors ◽  
High Level

AbstractLong non-coding RNAs (lncRNAs) play an important role in the regulation of key cellular processes in early development and in cancer. LncRNAOip5-as1facilitates stem cell self-renewal in mouse by sponging mmu-miR-7 and modulating NANOG level, yet its role in cancer is less understood. We analyzedOIP5-AS1expression in oral tumors and in TCGA datasets. We observed overexpression ofOIP5-AS1in oral tumors (P<0.001) and in tumors of epithelial origin from TCGA.OIP5-AS1expression was strongly associated with undifferentiated tumors (P=0.0038).In silicoanalysis showed miR-7 binding site is conserved in mouse and humanOIP5-AS1. However, humanNANOG3’-UTR lost the binding site for hsa-miR-7a-3. Therefore, we screened for other miRNAs that can be sponged byOIP5-AS1and identified six potential miRNAs and their downstream target genes. Expression analysis showed downregulation of miRNAs and upregulation of downstream target genes, particularly in undifferentiated tumors with high-level ofOIP5-AS1suggesting thatOIP5-AS1could post-transcriptionally modulate the downstream target genes. Further, systematic epigenomic analysis ofOIP5-AS1promoter revealed binding motifs for MYC, NANOG and KLF4 suggesting thatOIP5-AS1could be transactivated by stemness-associated transcription factors in cancer. Overexpression of OIP5-AS1 in undifferentiated oral tumors may confer poor prognosis through maintenance of cancer stemness.

scholarly journals The family feud: turning off Sp1 by Sp1-like KLF proteins

2005 ◽  
Vol 392 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Gwen Lomberk ◽  
Raul Urrutia
Keyword(s):  
Transcription Factors ◽  
Extended Family ◽  
Zinc Fingers ◽  
Dna Binding Domain ◽  
Transcriptional Activators ◽  
Transcriptional Repressors ◽  
Biological Functions ◽  
Cellular Processes ◽  
The Family ◽  
Number Of Genes

Sp1 is one of the best characterized transcriptional activators. The biological importance of Sp1 is underscored by the fact that several hundreds of genes are thought to be regulated by this protein. However, during the last 5 years, a more extended family of Sp1-like transcription factors has been identified and characterized by the presence of a conserved DNA-binding domain comprising three Krüppel-like zinc fingers. Each distinct family member differs in its ability to regulate transcription, and, as a consequence, to influence cellular processes. Specific activation and repression domains located within the N-terminal regions of these proteins are responsible for these differences by facilitating interactions with various co-activators and co-repressors. The present review primarily focuses on discussing the structural, biochemical and biological functions of the repressor members of this family of transcription factors. The existence of these transcriptional repressors provides a tightly regulated mechanism for silencing a large number of genes that are already known to be activated by Sp1.

scholarly journals Using CRISPRa and CRISPRi Technologies to Study the Biological Functions of ITGB5, TIMP1, and TMEM176B in Prostate Cancer Cells

2021 ◽  
Vol 8 ◽  
Author(s):  
Yi Yang ◽  
Qingxing Feng ◽  
Kun Hu ◽  
Feng Cheng
Keyword(s):  
Prostate Cancer ◽  
Gene Regulation ◽  
Transcription Factors ◽  
Cancer Cells ◽  
Biological Functions ◽  
Prostate Cancer Cells ◽  
Biological Mechanisms ◽  
Invasion And Migration ◽  
And Migration ◽  
Crispr Activation

Although ITGB5, TIMP1, and TMEM176B are abnormally expressed in several cancers, their molecular biological mechanisms in prostate cancer cells are still to be investigated. The gene regulation technogies based on CRISPR transcription factors could be used to investigate the biological functions of genes in cancer. In this study, we used CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) technologies to regulate the transcription of ITGB5, TIMP1, and TMEM176B in prostate cancer cells. Through a series of cellualr experiments, we found that inhibition of ITGB5 or activation of TIMP1 and TMEM176B suppress prostate cancer. The three genes synergistically affect the proliferation, invasion and migration capabilities of cancer cells.

scholarly journals Extracellular Signal-Regulated Kinase Signaling Regulates the Opposing Roles of JUN Family Transcription Factors at ETS/AP-1 Sites and in Cell Migration

2014 ◽  
Vol 35 (1) ◽  
pp. 88-100 ◽  
Author(s):  
Nagarathinam Selvaraj ◽  
Justin A. Budka ◽  
Mary W. Ferris ◽  
Joshua P. Plotnik ◽  
Peter C. Hollenhorst
Keyword(s):  
Transcription Factors ◽  
Cell Migration ◽  
Target Genes ◽  
Regulatory Elements ◽  
Erk Signaling ◽  
Prostate Cell ◽  
Extracellular Signal Regulated Kinase ◽  
Cellular Processes ◽  
Extracellular Signal ◽  
Biological Phenotype

JUN transcription factors bind DNA as part of the AP-1 complex, regulate many cellular processes, and play a key role in oncogenesis. The three JUN proteins (c-JUN, JUNB, and JUND) can have both redundant and unique functions depending on the biological phenotype and cell type assayed. Mechanisms that allow this dynamic switching between overlapping and distinct functions are unclear. Here we demonstrate that JUND has a role in prostate cell migration that is the opposite of c-JUN’s and JUNB's. RNA sequencing reveals that opposing regulation by c-JUN and JUND defines a subset of AP-1 target genes with cell migration roles.cis-regulatory elements for only this subset of targets were enriched for ETS factor binding, indicating a specificity mechanism. Interestingly, the function of c-JUN and JUND in prostate cell migration switched when we compared cells with an inactive versus an active RAS/extracellular signal-regulated kinase (ERK) signaling pathway. We show that this switch is due to phosphorylation and activation of JUND by ERK. Thus, the ETS/AP-1 sequence defines a unique gene expression program regulated by the relative levels of JUN proteins and RAS/ERK signaling. This work provides a rationale for how transcription factors can have distinct roles depending on the signaling status and the biological function in question.

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