scholarly journals Complexities in the role of acetylation dynamics in modifying inducible gene activation parameters

2021 ◽  
Author(s):  
Samantha Carrera ◽  
Amanda O'Donnell ◽  
Yaoyong Li ◽  
Karol Nowicki-Osuch ◽  
Syed Murtuza Baker ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Gene Activation ◽  
Transcriptional Response ◽  
Activation Parameters ◽  
Regulatory Elements ◽  
Lysine Acetylation ◽  
Efficient Gene ◽  
Inducible Genes ◽  
Target Gene Induction ◽  
Inducible Gene

High levels of histone acetylation are associated with the regulatory elements of active genes, suggesting a link between acetylation and gene activation. However, several studies have shown that histone acetylation dynamics rather than hyperacetylation per se are important determinants in gene activation, particularly at inducible genes. We revisited this model, in the context of EGF-inducible gene expression and found that rather than a simple unifying model, there are two broad classes of genes; one in which high lysine acetylation activity is required for efficient gene activation, and a second group where the opposite occurs and high acetylation activity is inhibitory. We examined the latter class in more detail using EGR2 as a model gene and found that lysine acetylation levels are critical for several activation parameters, including the timing of expression onset, and overall amplitudes of the transcriptional response. In contrast, DUSP1 responds in the canonical manner and its transcriptional activity is promoted by acetylation. Single cell approaches demonstrate heterogenous DUSP1 activation kinetics and that acetylation levels influence allele activation frequencies. Our data therefore point to a complex interplay between acetylation dynamics and target gene induction, which cannot simply be explained by a unified response to acetylation activity. Instead, acetylation level thresholds are an important determinant of transcriptional induction dynamics that are sensed in a gene-specific manner.

scholarly journals Plenary Lecture 2 Transcription factors, regulatory elements and nutrient–gene communication

2009 ◽  
Vol 69 (1) ◽  
pp. 91-94 ◽  
Author(s):  
Robert J. Cousins ◽  
Tolunay B. Aydemir ◽  
Louis A. Lichten
Keyword(s):  
Transcription Factors ◽  
Histone Acetylation ◽  
Intracellular Transport ◽  
Molecular Mechanisms ◽  
Gene Activation ◽  
Regulatory Elements ◽  
Atp Citrate Lyase ◽  
Signalling Molecules ◽  
Citrate Lyase ◽  
Normal Metabolism

Dramatic advances have been made in the understanding of the differing molecular mechanisms used by nutrients to regulate genes that are essential for their biological roles to carry out normal metabolism. Classical studies have focused on nutrients as ligands to activate specific transcription factors. New interest has focused on histone acetylation as a process for either global or limited gene activation and is the first mechanism to be discussed. Nuclear ATP-citrate lyase generates acetyl-CoA, which has been shown to have a role in the activation of specific genes via selective histone acetylation. Transcription factor acetylation may provide a second mode of control of nutrient-responsive gene transcription. The third mechanism relates to the availability of response elements within chromatin, which as well as the location of the elements in the gene may allow or prevent transcription. A fourth mechanism involves intracellular transport of Zn ions, which can orchestrate localized enzyme inhibition–activation. This process in turn influences signalling molecules that regulate gene expression. The examples provided in the present review point to a new level of complexity in understanding nutrient–gene communication.

scholarly journals GCN5 enables HSP12 induction promoting chromatin remodeling not histone acetylation.

2021 ◽  
Author(s):  
Francesca Antonazzi ◽  
Francesca Di Felice ◽  
Giorgio Camilloni
Keyword(s):  
Oxidative Stress ◽  
Heat Shock ◽  
Histone Acetylation ◽  
Chromatin Remodeling ◽  
Gene Activation ◽  
Transcriptional Response ◽  
Regulation Of Transcription ◽  
Molecular Response ◽  
H2o2 Treatment ◽  
Shock Response

Regulation of stress responsive genes represents one of the best examples of gene induction and the relevance and involvement of different regulators may change for a given gene depending on the challenging stimulus. HSP12 gene is induced by very different stimuli, however the molecular response to the stress has been characterized in detail only for heat shock treatments. In this work we want to verify whether, the regulation of transcription induced by oxidative stress, utilizes the same epigenetic solutions relative to those employed in heat shock response. We also monitored HSP12 induction employing spermidine, a known acetyltransferase inhibitor, and observed an oxidative stress that synergizes with spermidine treatment. Our data show that during transcriptional response to H2O2, histone acetylation and chromatin remodeling occur. However, when the relevance of Gcn5p on these processes was studied, we observed that induction of transcription is GCN5 dependent and this does not rely on histone acetylation by Gcn5p despite its HAT activity. Chromatin remodeling accompanying gene activation is rather GCN5 dependent. Thus, GCN5 controls HSP12 transcription after H2O2 treatment by allowing chromatin remodeling and it is only partially involved in HSP12 histone acetylation regardless its HAT activity.

scholarly journals ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jie Li ◽  
Phillip M. Galbo ◽  
Weida Gong ◽  
Aaron J. Storey ◽  
Yi-Hsuan Tsai ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Fusion Gene ◽  
Ex Vivo ◽  
Chromosomal Translocation ◽  
Regulatory Elements ◽  
Hematopoietic Stem ◽  
Its Gene ◽  
Human Acute Myeloid Leukemia ◽  
Bromodomain Proteins

AbstractRecurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-‘reading’ bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.

scholarly journals Double-inducible gene activation system for caspase 3 and 9 in epidermis

genesis ◽  
2007 ◽  
Vol 45 (4) ◽  
pp. 194-199 ◽  
Author(s):  
Viraj R. Shah ◽  
Maranke I. Koster ◽  
Dennis R. Roop ◽  
David M. Spencer ◽  
Lei Wei ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Gene Activation ◽  
Activation System ◽  
Inducible Gene

scholarly journals Low-affinity transcription factor binding sites shape morphogen responses and enhancer evolution

2013 ◽  
Vol 368 (1632) ◽  
pp. 20130018 ◽  
Author(s):  
Andrea I. Ramos ◽  
Scott Barolo
Keyword(s):  
Transcription Factor ◽  
Binding Affinity ◽  
Binding Sites ◽  
Target Genes ◽  
Gene Activation ◽  
Transcriptional Response ◽  
Morphogen Gradients ◽  
Weak Binding ◽  
Initial Hypothesis

In the era of functional genomics, the role of transcription factor (TF)–DNA binding affinity is of increasing interest: for example, it has recently been proposed that low-affinity genomic binding events, though frequent, are functionally irrelevant. Here, we investigate the role of binding site affinity in the transcriptional interpretation of Hedgehog (Hh) morphogen gradients . We noted that enhancers of several Hh-responsive Drosophila genes have low predicted affinity for Ci, the Gli family TF that transduces Hh signalling in the fly. Contrary to our initial hypothesis, improving the affinity of Ci/Gli sites in enhancers of dpp , wingless and stripe , by transplanting optimal sites from the patched gene, did not result in ectopic responses to Hh signalling. Instead, we found that these enhancers require low-affinity binding sites for normal activation in regions of relatively low signalling. When Ci/Gli sites in these enhancers were altered to improve their binding affinity, we observed patterning defects in the transcriptional response that are consistent with a switch from Ci-mediated activation to Ci-mediated repression. Synthetic transgenic reporters containing isolated Ci/Gli sites confirmed this finding in imaginal discs. We propose that the requirement for gene activation by Ci in the regions of low-to-moderate Hh signalling results in evolutionary pressure favouring weak binding sites in enhancers of certain Hh target genes.

scholarly journals Decoding an organ regeneration switch by dissecting cardiac regeneration enhancers

Development ◽  
2020 ◽  
Vol 147 (24) ◽  
pp. dev194019
Author(s):  
Ian J. Begeman ◽  
Kwangdeok Shin ◽  
Daniel Osorio-Méndez ◽  
Andrew Kurth ◽  
Nutishia Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tissue Regeneration ◽  
Cardiac Injury ◽  
Transcriptional Response ◽  
Cardiac Regeneration ◽  
Regulatory Elements ◽  
Heart Regeneration ◽  
New Paradigm ◽  
Closely Related Species ◽  
Organ Regeneration

ABSTRACTHeart regeneration in regeneration-competent organisms can be accomplished through the remodeling of gene expression in response to cardiac injury. This dynamic transcriptional response relies on the activities of tissue regeneration enhancer elements (TREEs); however, the mechanisms underlying TREEs are poorly understood. We dissected a cardiac regeneration enhancer in zebrafish to elucidate the mechanisms governing spatiotemporal gene expression during heart regeneration. Cardiac lepb regeneration enhancer (cLEN) exhibits dynamic, regeneration-dependent activity in the heart. We found that multiple injury-activated regulatory elements are distributed throughout the enhancer region. This analysis also revealed that cardiac regeneration enhancers are not only activated by injury, but surprisingly, they are also actively repressed in the absence of injury. Our data identified a short (22 bp) DNA element containing a key repressive element. Comparative analysis across Danio species indicated that the repressive element is conserved in closely related species. The repression mechanism is not operational during embryogenesis and emerges when the heart begins to mature. Incorporating both activation and repression components into the mechanism of tissue regeneration constitutes a new paradigm that might be extrapolated to other regeneration scenarios.

Molecular Model of the Interaction Between the Glucocorticoid Receptor and the Regulatory Elements of Inducible Genes

DNA ◽  
1986 ◽  
Vol 5 (5) ◽  
pp. 383-391 ◽  
Author(s):  
CLAUS SCHEIDEREIT ◽  
HANNES M. WESTPHAL ◽  
CHRISTOPHER CARLSON ◽  
HEINZ BOSSHARD ◽  
MIGUEL BEATO
Keyword(s):  
Glucocorticoid Receptor ◽  
Molecular Model ◽  
Regulatory Elements ◽  
Inducible Genes

scholarly journals Specific chromatin changes mark lateral organ founder cells in the Arabidopsis inflorescence meristem

2019 ◽  
Vol 70 (15) ◽  
pp. 3867-3879 ◽  
Author(s):  
Anneke Frerichs ◽  
Julia Engelhorn ◽  
Janine Altmüller ◽  
Jose Gutierrez-Marcos ◽  
Wolfgang Werr
Keyword(s):  
Dna Sequences ◽  
High Throughput Sequencing ◽  
Gene Activation ◽  
Regulatory Elements ◽  
Inflorescence Meristem ◽  
Genome Wide ◽  
A Genome ◽  
Hypersensitive Sites ◽  
Lateral Organ ◽  
Founder Cells

Abstract Fluorescence-activated cell sorting (FACS) and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) were combined to analyse the chromatin state of lateral organ founder cells (LOFCs) in the peripheral zone of the Arabidopsis apetala1-1 cauliflower-1 double mutant inflorescence meristem. On a genome-wide level, we observed a striking correlation between transposase hypersensitive sites (THSs) detected by ATAC-seq and DNase I hypersensitive sites (DHSs). The mostly expanded DHSs were often substructured into several individual THSs, which correlated with phylogenetically conserved DNA sequences or enhancer elements. Comparing chromatin accessibility with available RNA-seq data, THS change configuration was reflected by gene activation or repression and chromatin regions acquired or lost transposase accessibility in direct correlation with gene expression levels in LOFCs. This was most pronounced immediately upstream of the transcription start, where genome-wide THSs were abundant in a complementary pattern to established H3K4me3 activation or H3K27me3 repression marks. At this resolution, the combined application of FACS/ATAC-seq is widely applicable to detect chromatin changes during cell-type specification and facilitates the detection of regulatory elements in plant promoters.

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