scholarly journals GLI transcriptional repression regulates tissue-specific enhancer activity in response to Hedgehog signaling

2019 ◽  
Author(s):  
Rachel K. Lex ◽  
Zhicheng Ji ◽  
Kristin N. Falkenstein ◽  
Weiqiang Zhou ◽  
Joanna L. Henry ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Hedgehog Signaling ◽  
Target Gene ◽  
Target Genes ◽  
Enhancer Activity ◽  
Tissue Specific ◽  
Major Mechanism ◽  
Gli Proteins ◽  
Polycomb Repression ◽  
Repression Complex

ABSTRACTTranscriptional repression needs to be rapidly reversible during embryonic development. This extends to the Hedgehog pathway, which primarily serves to counter GLI repression by processing GLI proteins into transcriptional activators. In investigating the mechanisms underlying GLI repression, we find that a subset of these regions, termed HH-responsive enhancers, specifically loses acetylation in the absence of HH signaling. These regions are highly enriched around HH target genes and primarily drive HH-specific limb activity. They also retain H3K27ac enrichment in limb buds devoid of GLI activator and repressor, indicating that their activity is primarily regulated by GLI repression. The Polycomb repression complex is not active at most of these regions, suggesting it is not a major mechanism of GLI repression. We propose a model for tissue-specific enhancer activity in which an HDAC-associated GLI repression complex regulates target gene expression by altering the acetylation status at enhancers.

scholarly journals GLI transcriptional repression regulates tissue-specific enhancer activity in response to Hedgehog signaling

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Rachel K Lex ◽  
Zhicheng Ji ◽  
Kristin N Falkenstein ◽  
Weiqiang Zhou ◽  
Joanna L Henry ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Hedgehog Signaling ◽  
Target Genes ◽  
Limb Bud ◽  
Enhancer Activity ◽  
Tissue Specific ◽  
Major Mechanism ◽  
Gli Proteins ◽  
Repression Complex ◽  
Mouse Limb

Transcriptional repression needs to be rapidly reversible during embryonic development. This extends to the Hedgehog pathway, which primarily serves to counter GLI repression by processing GLI proteins into transcriptional activators. In investigating the mechanisms underlying GLI repression, we find that a subset of GLI binding regions, termed HH-responsive enhancers, specifically loses acetylation in the absence of HH signaling. These regions are highly enriched around HH target genes and primarily drive HH-specific transcriptional activity in the mouse limb bud. They also retain H3K27ac enrichment in limb buds devoid of GLI activator and repressor, indicating that their activity is primarily regulated by GLI repression. Furthermore, the Polycomb repression complex is not active at most of these regions, suggesting it is not a major mechanism of GLI repression. We propose a model for tissue-specific enhancer activity in which an HDAC-associated GLI repression complex regulates target genes by altering the acetylation status at enhancers.

scholarly journals Author response: GLI transcriptional repression regulates tissue-specific enhancer activity in response to Hedgehog signaling

2019 ◽  
Author(s):  
Rachel K Lex ◽  
Zhicheng Ji ◽  
Kristin N Falkenstein ◽  
Weiqiang Zhou ◽  
Joanna L Henry ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Hedgehog Signaling ◽  
Author Response ◽  
Enhancer Activity ◽  
Tissue Specific

scholarly journals GLI transcriptional repression is inert prior to Hedgehog pathway activation

2021 ◽  
Author(s):  
Rachel K. Lex ◽  
Weiqiang Zhou ◽  
Zhicheng Ji ◽  
Kristin N. Falkenstein ◽  
Kaleigh E. Schuler ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Limb Development ◽  
Target Genes ◽  
Hedgehog Pathway ◽  
Transcriptional Repressors ◽  
Posterior Limb ◽  
Gli Proteins ◽  
Pathway Activation ◽  
Hh Signaling ◽  
Anterior Posterior

In the absence of Hedgehog (HH) signaling, GLI proteins are post-translationally modified within cilia into transcriptional repressors that subsequently prevent sub-threshold activation of HH target genes. GLI repression is presumably important for preventing precocious expression of target genes before the onset of HH pathway activation, a presumption that underlies the pre-patterning model of anterior-posterior limb polarity. Here, we report that GLI3 repressor is abundant and binds to target genes in early limb development. However, contrary to expectations, GLI3 repression neither regulates the activity of GLI enhancers nor expression of HH target genes as it does after HH signaling has been established. Within the cilia, the transition to active GLI repression is accompanied by increases in axonemal GLI3 localization, possibly signifying altered GLI3 processing. Together, our results demonstrate that GLI3 repression does not prevent precocious activation of HH target genes, or have a pre-patterning role in regulating anterior-posterior limb polarity.

scholarly journals Polycomb-group recruitment to a Drosophila target gene is the default state that is inhibited by a transcriptional activator

2021 ◽  
Vol 7 (29) ◽  
pp. eabg1556
Author(s):  
Elnaz Ghotbi ◽  
Piao Ye ◽  
Taylor Ervin ◽  
Anni Kum ◽  
Judith Benes ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Target Gene ◽  
Target Genes ◽  
De Novo ◽  
Polycomb Group ◽  
Polycomb Repressive Complex 2 ◽  
Repressive Chromatin ◽  
Group Recruitment ◽  
Default State ◽  
Present Experimental Evidence

Polycomb-group (PcG) proteins are epigenetic regulators that maintain the transcriptional repression of target genes following their initial repression by transcription factors. PcG target genes are repressed in some cells, but active in others. Therefore, a mechanism must exist by which PcG proteins distinguish between the repressed and active states and only assemble repressive chromatin environments at target genes that are repressed. Here, we present experimental evidence that the repressed state of a Drosophila PcG target gene, giant (gt), is not identified by the presence of a repressor. Rather, de novo establishment of PcG-mediated silencing at gt is the default state that is prevented by the presence of an activator or coactivator, which may inhibit the catalytic activity of Polycomb-repressive complex 2 (PRC2).

FLT3ITD Target Enhancers Are Primed but Inaccessible in Fetal Hematopoietic Progenitors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1228-1228
Author(s):  
Yanan Li ◽  
Riddhi M Patel ◽  
Emily Casey ◽  
Jeffrey A. Magee
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Target Gene ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Gene Activation ◽  
Chromatin Accessibility ◽  
Luciferase Reporter ◽  
Enhancer Activity ◽  
Target Gene Expression

The FLT3 Internal Tandem Duplication (FLT3ITD) is common somatic mutation in acute myeloid leukemia (AML). We have previously shown that FLT3ITD fails to induce changes in HSC self-renewal, myelopoiesis and leukemogenesis during fetal stages of life. FLT3ITD signal transduction pathways are hyperactivated in fetal progenitors, but FLT3ITD target genes are not. This suggests that postnatal-specific transcription factors may be required to help induce FLT3ITD target gene expression. Alternatively, repressive histone modifications may impose a barrier to FLT3ITD target gene activation in fetal HPCs that is relaxed during postnatal development. To resolve these possibilities, we used ATAC-seq, as well as H3K4me1, H3K27ac and H3K27me3 ChIP-seq, to identify cis-elements that putatively control FLT3ITD target gene expression in fetal and adult hematopoietic progenitor cells (HPCs). We identified many enhancer elements (ATAC-seq peaks with H3K4me1 and H3K27ac) that exhibited increased chromatin accessibility and activity in FLT3ITD adult HPCs relative to wild type adult HPCs. These elements were enriched near FLT3ITD target genes. HOMER analysis showed enrichment for STAT5, ETS, RUNX1 and IRF binding motifs within the FLT3ITD target enhancers, but motifs for temporally dynamic transcription factors were not identified. We cloned a subset of the enhancers and confirmed that they could synergize with their promoter to activate a luciferase reporter. For representative enhancers, STAT5 binding sites were required to activate the enhancer - as anticipated - and RUNX1 repressed enhancer activity. We tested whether accessibility or priming changed between fetal and adult stages of HPC development. FLT3ITD-dependent changes in chromatin accessibility were not observed in fetal HPCs, though the enhancers were primed early in development as evidenced by the presence of H3K4me1. Repressive H3K27me3 were not present at FLT3ITD target enhancers in either or adult HPCs. The data show that FLT3ITD target enhancers are demarcated early in hematopoietic development, long before they become responsive to FLT3ITD signaling. Repressive marks do not appear to create an epigenetic barrier to enhancer activation in the fetal stage. Instead, age-specific transcription factors are likely required to pioneer enhancer elements so that they can respond to STAT5 and other FLT3ITD effectors. Disclosures No relevant conflicts of interest to declare.

scholarly journals RBP-Jκ/SHARP Recruits CtIP/CtBP Corepressors To Silence Notch Target Genes

2005 ◽  
Vol 25 (23) ◽  
pp. 10379-10390 ◽  
Author(s):  
Franz Oswald ◽  
Michael Winkler ◽  
Ying Cao ◽  
Kathy Astrahantseff ◽  
Soizic Bourteele ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Target Gene ◽  
Animal Species ◽  
Target Genes ◽  
Dna Binding Protein ◽  
Dominant Negative ◽  
Cell Fates ◽  
Corepressor Complex ◽  
Necessary And Sufficient ◽  
Repression Domain

ABSTRACT Notch is a transmembrane receptor that determines cell fates and pattern formation in all animal species. After ligand binding, proteolytic cleavage steps occur and the intracellular part of Notch translocates to the nucleus, where it targets the DNA-binding protein RBP-Jκ/CBF1. In the absence of Notch, RBP-Jκ represses Notch target genes through the recruitment of a corepressor complex. We and others have identified SHARP as a component of this complex. Here, we functionally demonstrate that the SHARP repression domain is necessary and sufficient to repress transcription and that the absence of this domain causes a dominant negative Notch-like phenotype. We identify the CtIP and CtBP corepressors as novel components of the human RBP-Jκ/SHARP-corepressor complex and show that CtIP binds directly to the SHARP repression domain. Functionally, CtIP and CtBP augment SHARP-mediated repression. Transcriptional repression of the Notch target gene Hey1 is abolished in CtBP-deficient cells or after the functional knockout of CtBP. Furthermore, the endogenous Hey1 promoter is derepressed in CtBP-deficient cells. We propose that a corepressor complex containing CtIP/CtBP facilitates RBP-Jκ/SHARP-mediated repression of Notch target genes.

scholarly journals Zebrafish GPR161 Contributes to Basal Hedgehog Repression in a Tissue-specific Manner

2019 ◽  
Author(s):  
Philipp Tschaikner ◽  
Dominik Regele ◽  
Willi Salvenmoser ◽  
Stephan Geley ◽  
Eduard Stefan ◽  
...  
Keyword(s):  
Target Gene ◽  
Target Genes ◽  
Negative Regulator ◽  
Fine Tuning ◽  
Tissue Specific ◽  
Relative Contribution ◽  
Direct Patterning ◽  
High Level ◽  
Inappropriate Expression ◽  
G Protein Coupled

AbstractHedgehog (Hh) ligands act as morphogens to direct patterning and proliferation during embryonic development. Protein kinase A (PKA) is a central negative regulator of Hh signalling, and in the absence of Hh ligands, PKA activity prevents inappropriate expression of Hh target genes. The Gαs- coupled receptor Gpr161 contributes to the basal Hh repression machinery by activating PKA, although the extent of this contribution is unclear. Here we show that loss of Gpr161 in zebrafish leads to constitutive activation of low-, but not high-level Hh target gene expression in the neural tube. In contrast, in the myotome, both high- and low-level Hh signalling is constitutively activated in the absence of Gpr161 function. Our results suggest that the relative contribution of Gpr161 to basal repression of Hh signalling is tissue-specific. Distinct combinations of G-protein-coupled receptors may allow the fine-tuning of PKA activity to ensure the appropriate sensitivity to Hh across different tissues.

scholarly journals Wnt target enhancer regulation by a CDX/TCF transcription factor collective and a novel DNA motif

2021 ◽  
Author(s):  
Aravinda-Bharathi Ramakrishnan ◽  
Lisheng Chen ◽  
Peter Burby ◽  
Ken M. Cadigan
Keyword(s):  
Target Gene ◽  
Target Genes ◽  
Mechanisms Of Action ◽  
Wnt Signalling ◽  
Complex Nature ◽  
Enhancer Activity ◽  
Dna Motif ◽  
Responsive Element ◽  
Cis And Trans ◽  
Enhancer Regulation

AbstractTranscriptional regulation by Wnt signalling is primarily thought to be accomplished by a complex of β-catenin and TCF family transcription factors (TFs). Although numerous studies have suggested that additional TFs play roles in regulating Wnt target genes, their mechanisms of action have not been investigated in detail. We characterised a Wnt-responsive element (WRE) downstream of the Wnt target gene Axin2 and found that TCFs and Caudal-related homeodomain (CDX) proteins were required for its activation. Using a new separation-of-function TCF mutant, we found that WRE activity requires the formation of a TCF/CDX complex. Our systematic mutagenesis of this enhancer identified other sequences essential for activation by Wnt signalling, including several copies of a novel CAG DNA motif. Computational and experimental evidence indicates that the TCF/CDX/CAG mode of regulation is prevalent in multiple WREs. Put together, our results demonstrate the complex nature of cis- and trans- interactions required for signal-dependent enhancer activity.

Tissue-Specific TAFs Counteract Polycomb to Turn on Terminal Differentiation

Science ◽  
2005 ◽  
Vol 310 (5749) ◽  
pp. 869-872 ◽  
Author(s):  
Xin Chen ◽  
Mark Hiller ◽  
Yasemin Sancak ◽  
Margaret T. Fuller
Keyword(s):  
Germ Cells ◽  
Chromatin Immunoprecipitation ◽  
Target Gene ◽  
Terminal Differentiation ◽  
Male Germ Cells ◽  
Turn On ◽  
Polycomb Repression ◽  
Repression Complex ◽  
Target Promoters ◽  
Local Accumulation

Polycomb transcriptional silencing machinery is implicated in the maintenance of precursor fates, but how this repression is reversed to allow cell differentiation is unknown. Here we show that testis-specific TAF (TBP-associated factor) homologs required for terminal differentiation of male germ cells may activate target gene expression in part by counteracting repression by Polycomb. Chromatin immunoprecipitation revealed that testis TAFs bind to target promoters, reduce Polycomb binding, and promote local accumulation of H3K4me3, a mark of Trithorax action. Testis TAFs also promoted relocalization of Polycomb Repression Complex 1 components to the nucleolus in spermatocytes, implicating subnuclear architecture in the regulation of terminal differentiation.

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