Groucho mediates a Ci-independent mechanism of hedgehog repression in the anterior wing pouch

Development ◽  
2001 ◽  
Vol 128 (21) ◽  
pp. 4361-4370 ◽  
Author(s):  
Yiorgos Apidianakis ◽  
Diane Grbavec ◽  
Stefano Stifani ◽  
Christos Delidakis
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Embryonic Patterning ◽  
Loss Of Function ◽  
Cubitus Interruptus ◽  
Founding Member ◽  
Independent Mechanism ◽  
Wing Pouch ◽  
Wd40 Repeats ◽  
Multifunctional Transcription Factor

Groucho (Gro) is the founding member of a family of transcriptional co-repressors that are recruited by a number of different transcription factors. Drosophila has a single gro gene, whose loss of function affects processes ranging from sex determination to embryonic patterning and neuroblast specification. We have characterized a function of Gro in imaginal development, namely the repression of hedgehog (hh) in anterior wing pouch cells. hh encodes a secreted morphogen with potent patterning activities. In Drosophila thoracic appendages (legs, wings, halteres), hh is expressed in posterior compartments and induces the anteroposterior (AP) pattern organizer in the cells across the AP boundary. hh is repressed in anterior compartments at least partly via Ci[rep], a form of the multifunctional transcription factor Cubitus interruptus (Ci). We show that cells in the wing primordium close to the AP boundary need gro activity to maintain repression of hh transcription, whereas in more anterior cells gro is dispensable. This repressive function of Gro does not appear to be mediated by Ci[rep]. Analysis of mutant gro transgenes has revealed that the Q and WD40 domains are both necessary for hh repression. Yet, deletion of the WD40 repeats does not always abolish Gro activity. Our findings provide new insights both into the mechanisms of AP patterning of the wing and into the function of Gro.

scholarly journals Rescue of a developmental arrest caused by a C. elegans heat-shock transcription-factor mutation by loss of ribosomal S6-kinase activity

2018 ◽  
Author(s):  
Peter Chisnell ◽  
T. Richard Parenteau ◽  
Elizabeth Tank ◽  
Kaveh Ashrafi ◽  
Cynthia Kenyon
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Heat Shock ◽  
Heat Shock Transcription Factor ◽  
Adult Longevity ◽  
Loss Of Function ◽  
S6 Kinase ◽  
Heat Shock Transcription Factors ◽  
C Elegans ◽  
Developmental Arrest

AbstractThe widely conserved heat-shock response, regulated by heat shock transcription factors, is not only essential for cellular stress resistance and adult longevity, but also for proper development. However, the genetic mechanisms by which heat-shock transcription factors regulate development are not well understood. In C. elegans, we conducted an unbiased genetic screen to identify mutations that could ameliorate the developmental arrest phenotype of a heat-shock factor mutant. Here we show that loss of the conserved translational activator rsks-1/S6-Kinase, a downstream effector of TOR kinase, can rescue the developmental-arrest phenotype of hsf-1 partial loss-of-function mutants. Unexpectedly, we show that the rescue is not likely caused by reduced translation, nor to activation of any of a variety of stress-protective genes and pathways. Our findings identify an as-yet unexplained regulatory relationship between the heat-shock transcription factor and the TOR pathway during C. elegans’ development.

scholarly journals The transcription factor activity gradient (TAG) model: contemplating a contact-independent mechanism for enhancer–promoter communication

2021 ◽  
Author(s):  
Jonathan P. Karr ◽  
John J. Ferrie ◽  
Robert Tjian ◽  
Xavier Darzacq
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Regulatory Elements ◽  
Transcription Factor Activity ◽  
Factor Activity ◽  
New Model ◽  
Unresolved Question ◽  
Regulatory Information ◽  
Independent Mechanism ◽  
Coactivator P300

How distal cis-regulatory elements (e.g., enhancers) communicate with promoters remains an unresolved question of fundamental importance. Although transcription factors and cofactors are known to mediate this communication, the mechanism by which diffusible molecules relay regulatory information from one position to another along the chromosome is a biophysical puzzle—one that needs to be revisited in light of recent data that cannot easily fit into previous solutions. Here we propose a new model that diverges from the textbook enhancer–promoter looping paradigm and offer a synthesis of the literature to make a case for its plausibility, focusing on the coactivator p300.

Ultimate Precision: Targeting Cancer but Not Normal Self-replication

2018 ◽  
pp. 950-963 ◽  
Author(s):  
Vamsidhar Velcheti ◽  
David Schrump ◽  
Yogen Saunthararajah
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Terminal Differentiation ◽  
Loss Of Function ◽  
Partial Loss ◽  
Common Pathway ◽  
Lineage Differentiation ◽  
Self Replication ◽  
Pharmacologic Inhibition

Self-replication is the engine that drives all biologic evolution, including neoplastic evolution. A key oncotherapy challenge is to target this, the heart of malignancy, while sparing the normal self-replication mandatory for health and life. Self-replication can be demystified: it is activation of replication, the most ancient of cell programs, uncoupled from activation of lineage-differentiation, metazoan programs more recent in origin. The uncoupling can be physiologic, as in normal tissue stem cells, or pathologic, as in cancer. Neoplastic evolution selects to disengage replication from forward-differentiation where intrinsic replication rates are the highest, in committed progenitors that have division times measured in hours versus weeks for tissue stem cells, via partial loss of function in master transcription factors that activate terminal-differentiation programs (e.g., GATA4) or in the coactivators they use for this purpose (e.g., ARID1A). These loss-of-function mutations bias master transcription factor circuits, which normally regulate corepressor versus coactivator recruitment, toward corepressors (e.g., DNMT1) that repress rather than activate terminal-differentiation genes. Pharmacologic inhibition of the corepressors rebalances to coactivator function, activating lineage-differentiation genes that dominantly antagonize MYC (the master transcription factor coordinator of replication) to terminate malignant self-replication. Physiologic self-replication continues, because the master transcription factors in tissue stem cells activate stem cell, not terminal-differentiation, programs. Druggable corepressor proteins are thus the barriers between self-replicating cancer cells and the terminal-differentiation fates intended by their master transcription factor content. This final common pathway to oncogenic self-replication, being separate and distinct from the normal, offers the favorable therapeutic indices needed for clinical progress.

scholarly journals The BTB transcription factors ZBTB11 and ZFP131 maintain pluripotency by pausing POL II at pro-differentiation genes

2020 ◽  
Author(s):  
Görkem Garipler ◽  
Congyi Lu ◽  
Alexis Morrissey ◽  
Lorena S. Lopez-Zepeda ◽  
Simon E. Vidal ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Stem Cell ◽  
Transcription Factors ◽  
Embryonic Stem ◽  
Loss Of Function ◽  
Pluripotent Cells ◽  
Pol Ii ◽  
Crispr Screen ◽  
Rapid Activation ◽  
Factor Release

AbstractIn pluripotent cells, a delicate activation-repression balance maintains pro-differentiation genes ready for rapid activation. The identity of transcription factors (TFs) that specifically repress pro-differentiation genes remains obscure. By targeting ~1,700 TFs with CRISPR loss-of-function screen, we found that ZBTB11 and ZFP131 are required for embryonic stem cell (ESC) pluripotency. ZBTB11 and ZFP131 maintain promoter-proximally paused Polymerase II at pro-differentiation genes in ESCs. ZBTB11 or ZFP131 loss leads to NELF pausing factor release, an increase in H3K4me3, and transcriptional upregulation of genes associated with all three germ layers. Together, our results suggest that ZBTB11 and ZFP131 maintain pluripotency by preventing premature expression of pro-differentiation genes and present a generalizable framework to maintain cellular potency.One-sentence summaryA Transcription Factor-wide CRISPR screen identifies ZBTB11 and ZFP131 maintaining pluripotency by pausing POL II at pro-differentiation genes

scholarly journals Single-molecule conformational dynamics of a transcription factor reveals a continuum of binding modes controlling association and dissociation

2021 ◽  
Author(s):  
Wei Chen ◽  
Wei Lu ◽  
Peter G Wolynes ◽  
Elizabeth A Komives
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Single Molecule ◽  
Bound States ◽  
Conformational Dynamics ◽  
Conformational Ensemble ◽  
Binding Modes ◽  
Loss Of Function ◽  
Binding Domains

Abstract Binding and unbinding of transcription factors to DNA are kinetically controlled to regulate the transcriptional outcome. Control of the release of the transcription factor NF-κB from DNA is achieved through accelerated dissociation by the inhibitor protein IκBα. Using single-molecule FRET, we observed a continuum of conformations of NF-κB in free and DNA-bound states interconverting on the subseconds to minutes timescale, comparable to in vivo binding on the seconds timescale, suggesting that structural dynamics directly control binding kinetics. Much of the DNA-bound NF-κB is partially bound, allowing IκBα invasion to facilitate DNA dissociation. IκBα induces a locked conformation where the DNA-binding domains of NF-κB are too far apart to bind DNA, whereas a loss-of-function IκBα mutant retains the NF-κB conformational ensemble. Overall, our results suggest a novel mechanism with a continuum of binding modes for controlling association and dissociation of transcription factors.

scholarly journals The Snail transcription factor CES-1 regulates glutamatergic behavior in C. elegans

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0245587
Author(s):  
Lidia Park ◽  
Eric S. Luth ◽  
Kelsey Jones ◽  
Julia Hofer ◽  
Irene Nguyen ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Synaptic Plasticity ◽  
Ampa Receptor ◽  
Active Form ◽  
Cell Lineage ◽  
Receptor Expression ◽  
Loss Of Function ◽  
Major Mechanism

Regulation of AMPA-type glutamate receptor (AMPAR) expression and function alters synaptic strength and is a major mechanism underlying synaptic plasticity. Although transcription is required for some forms of synaptic plasticity, the transcription factors that regulate AMPA receptor expression and signaling are incompletely understood. Here, we identify the Snail family transcription factor ces-1 in an RNAi screen for conserved transcription factors that regulate glutamatergic behavior in C. elegans. ces-1 was originally discovered as a selective cell death regulator of neuro-secretory motor neuron (NSM) and I2 interneuron sister cells in C. elegans, and has almost exclusively been studied in the NSM cell lineage. We found that ces-1 loss-of-function mutants have defects in two glutamatergic behaviors dependent on the C. elegans AMPA receptor GLR-1, the mechanosensory nose-touch response and spontaneous locomotion reversals. In contrast, ces-1 gain-of-function mutants exhibit increased spontaneous reversals, and these are dependent on glr-1 consistent with these genes acting in the same pathway. ces-1 mutants have wild type cholinergic neuromuscular junction function, suggesting that they do not have a general defect in synaptic transmission or muscle function. The effect of ces-1 mutation on glutamatergic behaviors is not due to ectopic cell death of ASH sensory neurons or GLR-1-expressing neurons that mediate one or both of these behaviors, nor due to an indirect effect on NSM sister cell deaths. Rescue experiments suggest that ces-1 may act, in part, in GLR-1-expressing neurons to regulate glutamatergic behaviors. Interestingly, ces-1 mutants suppress the increased reversal frequencies stimulated by a constitutively-active form of GLR-1. However, expression of glr-1 mRNA or GFP-tagged GLR-1 was not decreased in ces-1 mutants suggesting that ces-1 likely promotes GLR-1 function. This study identifies a novel role for ces-1 in regulating glutamatergic behavior that appears to be independent of its canonical role in regulating cell death in the NSM cell lineage.

scholarly journals Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Katherine A Donovan ◽  
Jian An ◽  
Radosław P Nowak ◽  
Jingting C Yuan ◽  
Emma C Fink ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Birth Defects ◽  
Molecular Basis ◽  
Congenital Heart ◽  
Loss Of Function ◽  
Morning Sickness ◽  
Species Specific ◽  
Developmental Condition

In historical attempts to treat morning sickness, use of the drug thalidomide led to the birth of thousands of children with severe birth defects. Despite their teratogenicity, thalidomide and related IMiD drugs are now a mainstay of cancer treatment; however, the molecular basis underlying the pleiotropic biology and characteristic birth defects remains unknown. Here we show that IMiDs disrupt a broad transcriptional network through induced degradation of several C2H2 zinc finger transcription factors, including SALL4, a member of the spalt-like family of developmental transcription factors. Strikingly, heterozygous loss of function mutations in SALL4 result in a human developmental condition that phenocopies thalidomide-induced birth defects such as absence of thumbs, phocomelia, defects in ear and eye development, and congenital heart disease. We find that thalidomide induces degradation of SALL4 exclusively in humans, primates, and rabbits, but not in rodents or fish, providing a mechanistic link for the species-specific pathogenesis of thalidomide syndrome.

scholarly journals Calcium activates serum response factor-dependent transcription by a Ras- and Elk-1-independent mechanism that involves a Ca2+/calmodulin-dependent kinase.

1995 ◽  
Vol 15 (7) ◽  
pp. 3672-3684 ◽  
Author(s):  
C K Miranti ◽  
D D Ginty ◽  
G Huang ◽  
T Chatila ◽  
M E Greenberg
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Growth Factors ◽  
Serum Response Factor ◽  
Active Form ◽  
Response Factor ◽  
Transcriptional Responses ◽  
Pheochromocytoma Cell ◽  
Independent Mechanism ◽  
Serum Response

Enhanced levels of cytoplasmic Ca2+ due to membrane depolarization with elevated levels of KCl or exposure to the Ca2+ ionophore ionomycin stimulate serum response element (SRE)-dependent transcription in the pheochromocytoma cell line PC12. By using altered binding specificity mutants of transcription factors that bind to the SRE, it was demonstrated that in contrast to treatment with purified growth factors, such as nerve growth factor, the serum response factor (SRF), but not Elk-1, mediates Ca(2+)-regulated SRE-dependent transcription. Enhanced levels of cytoplasmic Ca2+ were found to trigger SRE-dependent transcription via a Ras-independent signaling pathway that appears to involve a Ca2+/calmodulin-dependent kinase (CaMK). Overexpression of a constitutively active form of CaMKIV stimulated SRF-dependent transcription. Taken together, these findings indicate that SRF is a versatile transcription factor that, when bound to the SRE, can function by distinct mechanisms and can mediate transcriptional responses to both CaMK- and Ras-dependent signaling pathways.

Transcriptional regulation of the Hedgehog effector CI by the zinc-finger gene combgap

Development ◽  
2000 ◽  
Vol 127 (19) ◽  
pp. 4095-4103 ◽  
Author(s):  
G.L. Campbell ◽  
A. Tomlinson
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Zinc Finger ◽  
Transcriptional Activation ◽  
Dna Binding Protein ◽  
Loss Of Function ◽  
Cubitus Interruptus ◽  
Anterior Compartment ◽  
Zinc Finger Gene ◽  
Animal Development

Members of the Hedgehog (HH) family of secreted signaling molecules specify cell fate during animal development by controlling the activity of members of the Gli family of zinc-finger transcription factors in responding cells. In Drosophila the Gli homolog, cubitus interruptus (CI), is expressed only in the anterior compartment where it represses targets such as the signaling molecule genes decapentaplegic (dpp) and wingless (wg). HH is expressed in the posterior and diffuses into the anterior where it antagonizes CI repression resulting in dpp and wg expression immediately anterior to the compartment border. Reducing CI levels results in misexpression of wg and dpp, while CI misexpression in the posterior disrupts differentiation. Thus, normal disc patterning requires high levels of CI in the anterior and the absence of CI in the posterior. Here we show that mutations in combgap (cg) result in deregulation of CI expression, which is now expressed at much lower levels and ubiquitously, i.e., also in the posterior. Consequently, cg mutants phenocopy ci loss-of-function mutants in the anterior and ci gain-of-function mutants in the posterior. cg encodes a putative DNA-binding protein that regulates both transcriptional activation and repression of the ci gene.

myoblasts incompetent encodes a zinc finger transcription factor required to specify fusion-competent myoblasts in Drosophila

Development ◽  
2002 ◽  
Vol 129 (1) ◽  
pp. 133-141 ◽  
Author(s):  
Mar Ruiz-Gómez ◽  
Nikola Coutts ◽  
Maximiliano L. Suster ◽  
Matthias Landgraf ◽  
Michael Bate
Keyword(s):  
Transcription Factor ◽  
Zinc Finger ◽  
Myoblast Fusion ◽  
Loss Of Function ◽  
Cubitus Interruptus ◽  
Zinc Finger Transcription Factor ◽  
General Pathway ◽  
Twist Expression ◽  
Fusion Competent Myoblasts ◽  
Normal Differentiation

We report a new gene, myoblasts incompetent, essential for normal myogenesis and myoblast fusion in Drosophila. myoblasts incompetent encodes a putative zinc finger transcription factor related to vertebrate Gli proteins and to Drosophila Cubitus interruptus. myoblasts incompetent is expressed in immature somatic and visceral myoblasts. Expression is predominantly in fusion-competent myoblasts and a loss-of-function mutation in myoblasts incompetent leads to a failure in the normal differentiation of these cells and a complete lack of myoblast fusion. In the mutant embryos, founder myoblasts differentiate normally and form mononucleate muscles, but genes that are specifically expressed in fusion-competent cells are not activated and the normal downregulation of twist expression in these cells fails to occur. In addition, fusion-competent myoblasts fail to express proteins characteristic of the general pathway of myogenesis such as myosin and Dmef2. Thus myoblasts incompetent appears to function specifically in the general pathway of myogenesis to control the differentiation of fusion-competent myoblasts.

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