RPA1 binding to NRF2 switches ARE-dependent transcriptional activation to ARE-NRE–dependent repression

NRF2 regulates cellular redox homeostasis, metabolic balance, and proteostasis by forming a dimer with small musculoaponeurotic fibrosarcoma proteins (sMAFs) and binding to antioxidant response elements (AREs) to activate target gene transcription. In contrast, NRF2-ARE–dependent transcriptional repression is unreported. Here, we describe NRF2-mediated gene repression via a specific seven-nucleotide sequence flanking the ARE, which we term the NRF2-replication protein A1 (RPA1) element (NRE). Mechanistically, RPA1 competes with sMAF for NRF2 binding, followed by interaction of NRF2-RPA1 with the ARE-NRE and eduction of promoter activity. Genome-wide in silico and RNA-seq analyses revealed this NRF2-RPA1-ARE-NRE complex mediates negative regulation of many genes with diverse functions, indicating that this mechanism is a fundamental cellular process. Notably, repression ofMYLK, which encodes the nonmuscle myosin light chain kinase, by the NRF2-RPA1-ARE-NRE complex disrupts vascular integrity in preclinical inflammatory lung injury models, illustrating the translational significance of NRF2-mediated transcriptional repression. Our findings reveal a gene-suppressive function of NRF2 and a subset of negatively regulated NRF2 target genes, underscoring the broad impact of NRF2 in physiological and pathological settings.

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Regulation of subtelomeric fungal secondary metabolite genes by H3K4me3 regulators CclA and KdmB

10.26686/wgtn.13150928.v1 ◽

2020 ◽

Author(s):

Yonathan Lukito ◽

T Chujo ◽

TK Hale ◽

W Mace ◽

LJ Johnson ◽

...

Keyword(s):

Secondary Metabolite ◽

Transcriptional Activation ◽

Transcriptional Repression ◽

Target Genes ◽

H3k4 Methylation ◽

Genome Wide ◽

H3k4me3 Mark ◽

Transcriptional Changes ◽

Histone H3k4 ◽

A Site

© 2019 John Wiley & Sons Ltd Studies on the regulation of fungal secondary metabolism highlight the importance of histone H3K4 methylation regulators Set1, CclA (Ash2) and KdmB (KDM5), but it remains unclear whether these proteins act by direct modulation of H3K4me3 at the target genes. In filamentous fungi, secondary metabolite genes are frequently located near telomeres, a site where H3K4 methylation is thought to have a repressive role. Here we analyzed the role of CclA, KdmB and H3K4me3 in regulating the subtelomeric EAS and LTM cluster genes in Epichloë festucae. Depletion of H3K4me3 correlated with transcriptional activation of these genes in ΔcclA, similarly enrichment of H3K4me3 correlated with transcriptional repression of the genes in ΔkdmB which was accompanied by significant reduction in the levels of the agriculturally undesirable lolitrems. These transcriptional changes could only be explained by the alterations in H3K4me3 and not in the subtelomerically-important marks H3K9me3/K27me3. However, H3K4me3 changes in both mutants were not confined to these regions but occurred genome-wide, and at other subtelomeric loci there were inconsistent correlations between H3K4me3 enrichment and gene repression. Our study suggests that CclA and KdmB are crucial regulators of secondary metabolite genes, but these proteins likely act via means independent to, or in conjunction with the H3K4me3 mark.

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Regulation of subtelomeric fungal secondary metabolite genes by H3K4me3 regulators CclA and KdmB

10.26686/wgtn.13150928 ◽

2020 ◽

Author(s):

Yonathan Lukito ◽

T Chujo ◽

TK Hale ◽

W Mace ◽

LJ Johnson ◽

...

Keyword(s):

Secondary Metabolite ◽

Transcriptional Activation ◽

Transcriptional Repression ◽

Target Genes ◽

H3k4 Methylation ◽

Genome Wide ◽

H3k4me3 Mark ◽

Transcriptional Changes ◽

Histone H3k4 ◽

A Site

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ZFARED: A Database of the Antioxidant Response Elements in Zebrafish

Current Bioinformatics ◽

10.2174/1574893614666191018172213 ◽

2020 ◽

Vol 15 (5) ◽

pp. 415-419

Author(s):

Azhwar Raghunath ◽

Raju Nagarajan ◽

Ekambaram Perumal

Keyword(s):

Target Genes ◽

Antioxidant Response ◽

Zebrafish Genome ◽

Promoter Regions ◽

Protein Coding ◽

Response Elements ◽

Toxic Agents ◽

Upstream Promoter ◽

Its Gene ◽

Antioxidant Response Elements

Background: Antioxidant Response Elements (ARE) play a key role in the expression of Nrf2 target genes by regulating the Keap1-Nrf2-ARE pathway, which offers protection against toxic agents and oxidative stress-induced diseases. Objective: To develop a database of putative AREs for all the genes in the zebrafish genome. This database will be helpful for researchers to investigate Nrf2 regulatory mechanisms in detail. Methods: To facilitate researchers functionally characterize zebrafish AREs, we have developed a database of AREs, Zebrafish Antioxidant Response Element Database (ZFARED), for all the protein-coding genes including antioxidant and mitochondrial genes in the zebrafish genome. The front end of the database was developed using HTML, JavaScript, and CSS and tested in different browsers. The back end of the database was developed using Perl scripts and Perl-CGI and Perl- DBI modules. Results: ZFARED is the first database on the AREs in zebrafish, which facilitates fast and efficient searching of AREs. AREs were identified using the in-house developed Perl algorithms and the database was developed using HTML, JavaScript, and Perl-CGI scripts. From this database, researchers can access the AREs based on chromosome number (1 to 25 and M for mitochondria), strand (positive or negative), ARE pattern and keywords. Users can also specify the size of the upstream/promoter regions (5 to 30 kb) from transcription start site to access the AREs located in those specific regions. Conclusion: ZFARED will be useful in the investigation of the Keap1-Nrf2-ARE pathway and its gene regulation. ZFARED is freely available at http://zfared.buc.edu.in/.

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Dynamic histone acetylation in floral volatile synthesis and emission in petunia flowers

Journal of Experimental Botany ◽

10.1093/jxb/erab072 ◽

2021 ◽

Author(s):

Ryan M Patrick ◽

Xing-Qi Huang ◽

Natalia Dudareva ◽

Ying Li

Keyword(s):

Transcriptional Activation ◽

Metabolic Pathways ◽

Transcriptional Repression ◽

Metabolic Networks ◽

Underlying Mechanism ◽

Expression Of Genes ◽

Genome Wide ◽

Chemical Inhibitors ◽

Volatile Organic ◽

Floral Volatile

Abstract Biosynthesis of secondary metabolites relies on primary metabolic pathways to provide precursors, energy, and cofactors, thus requiring coordinated regulation of primary and secondary metabolic networks. However, to date, it remains largely unknown how this coordination is achieved. Using Petunia hybrida flowers, which emit high levels of phenylpropanoid/benzenoid volatile organic compounds (VOCs), we uncovered genome-wide dynamic deposition of histone H3 lysine 9 acetylation (H3K9ac) during anthesis as an underlying mechanism to coordinate primary and secondary metabolic networks. The observed epigenome reprogramming is accompanied by transcriptional activation at gene loci involved in primary metabolic pathways that provide precursor phenylalanine, as well as secondary metabolic pathways to produce volatile compounds. We also observed transcriptional repression among genes involved in alternative phenylpropanoid branches that compete for metabolic precursors. We show that GNAT family histone acetyltransferase(s) (HATs) are required for the expression of genes involved in VOC biosynthesis and emission, by using chemical inhibitors of HATs, and by knocking down a specific HAT gene, ELP3, through transient RNAi. Together, our study supports that regulatory mechanisms at chromatin level may play an essential role in activating primary and secondary metabolic pathways to regulate VOC synthesis in petunia flowers.

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Genome-Wide Analysis Reveals PADI4 Facilitates Transcriptional Activation of a Subset of Elk-1 Target Genes in MCF-7 Cells.

10.1210/endo-meetings.2010.part1.p3.p1-108 ◽

2010 ◽

pp. P1-108-P1-108

Author(s):

XS Zhang ◽

MJ Gamble ◽

S Stadler ◽

BD Cherrington ◽

MS Roberson ◽

...

Keyword(s):

Transcriptional Activation ◽

Target Genes ◽

Genome Wide Analysis ◽

Genome Wide ◽

Mcf 7

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Central clock components modulate plant shade avoidance by directly repressing transcriptional activation activity of PIF proteins

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1918317117 ◽

2020 ◽

Vol 117 (6) ◽

pp. 3261-3269 ◽

Cited By ~ 10

Author(s):

Yu Zhang ◽

Anne Pfeiffer ◽

James M. Tepperman ◽

Jutta Dalton-Roesler ◽

Pablo Leivar ◽

...

Keyword(s):

Transcriptional Activation ◽

Target Genes ◽

Direct Action ◽

Published Data ◽

Shade Avoidance ◽

Response Regulators ◽

Genome Wide ◽

Promoter Occupancy ◽

Factor Abundance ◽

Direct Target

Light-environment signals, sensed by plant phytochrome photoreceptors, are transduced to target genes through direct regulation of PHYTOCHROME-INTERACTING FACTOR (PIF) transcription factor abundance and activity. Previous genome-wide DNA-binding and expression analysis has identified a set of genes that are direct targets of PIF transcriptional regulation. However, quantitative analysis of promoter occupancy versus expression level has suggested that unknown “trans factors” modulate the intrinsic transcriptional activation activity of DNA-bound PIF proteins. Here, using computational analysis of published data, we have identified PSEUDO-RESPONSE REGULATORS (PRR5 and PRR7) as displaying a high frequency of colocalization with the PIF proteins at their binding sites in the promoters of PIF Direct Target Genes (DTGs). We show that the PRRs function to suppress PIF-stimulated growth in the light and vegetative shade and that they repress the rapid PIF-induced expression of PIF-DTGs triggered by exposure to shade. The repressive action of the PRRs on both growth and DTG expression requires the PIFs, indicating direct action on PIF activity, rather than a parallel antagonistic pathway. Protein interaction assays indicate that the PRRs exert their repressive activity by binding directly to the PIF proteins in the nucleus. These findings support the conclusion that the PRRs function as direct outputs from the core circadian oscillator to regulate the expression of PIF-DTGs through modulation of PIF transcriptional activation activity, thus expanding the roles of the multifunctional PIF-signaling hub.

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Role of co-regulators in metabolic and transcriptional actions of thyroid hormone

Journal of Molecular Endocrinology ◽

10.1530/jme-15-0246 ◽

2016 ◽

Vol 56 (3) ◽

pp. R73-R97 ◽

Cited By ~ 18

Author(s):

Inna Astapova

Keyword(s):

Thyroid Hormone ◽

Transcriptional Repression ◽

Target Genes ◽

Thyroid Hormone Receptor ◽

Retinoic Acid Receptor ◽

Specific Response ◽

Physiological Processes ◽

Genome Wide ◽

Wide Range ◽

And Function

Thyroid hormone (TH) controls a wide range of physiological processes through TH receptor (TR) isoforms. Classically, TRs are proposed to function as tri-iodothyronine (T3)-dependent transcription factors: on positively regulated target genes, unliganded TRs mediate transcriptional repression through recruitment of co-repressor complexes, while T3binding leads to dismissal of co-repressors and recruitment of co-activators to activate transcription. Co-repressors and co-activators were proposed to play opposite roles in the regulation of negative T3target genes and hypothalamic–pituitary–thyroid axis, but exact mechanisms of the negative regulation by TH have remained elusive. Important insights into the roles of co-repressors and co-activators in different physiological processes have been obtained using animal models with disrupted co-regulator function. At the same time, recent studies interrogating genome-wide TR binding have generated compelling new data regarding effects of T3, local chromatin structure, and specific response element configuration on TR recruitment and function leading to the proposal of new models of transcriptional regulation by TRs. This review discusses data obtained in various mouse models with manipulated function of nuclear receptor co-repressor (NCoR or NCOR1) and silencing mediator of retinoic acid receptor and thyroid hormone receptor (SMRT or NCOR2), and family of steroid receptor co-activators (SRCs also known as NCOAs) in the context of TH action, as well as insights into the function of co-regulators that may emerge from the genome-wide TR recruitment analysis.

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Nestin regulates cellular redox homeostasis in lung cancer through the Keap1–Nrf2 feedback loop

Nature Communications ◽

10.1038/s41467-019-12925-9 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 6

Author(s):

Jiancheng Wang ◽

Qiying Lu ◽

Jianye Cai ◽

Yi Wang ◽

Xiaofan Lai ◽

...

Keyword(s):

Oxidative Stress ◽

Lung Cancer ◽

Feedback Loop ◽

Redox Homeostasis ◽

Antioxidant Response ◽

Cellular Redox ◽

Anti Cancer ◽

Oxidative Stress Status ◽

Kelch Domain ◽

Antioxidant Response Elements

Abstract Abnormal cancer antioxidant capacity is considered as a potential mechanism of tumor malignancy. Modulation of oxidative stress status is emerging as an anti-cancer treatment. Our previous studies have found that Nestin-knockdown cells were more sensitive to oxidative stress in non-small cell lung cancer (NSCLC). However, the molecular mechanism by which Nestin protects cells from oxidative damage remains unclear. Here, we identify a feedback loop between Nestin and Nrf2 maintaining the redox homeostasis. Mechanistically, the ESGE motif of Nestin interacts with the Kelch domain of Keap1 and competes with Nrf2 for Keap1 binding, leading to Nrf2 escaping from Keap1-mediated degradation, subsequently promoting antioxidant enzyme generation. Interestingly, we also map that the antioxidant response elements (AREs) in the Nestin promoter are responsible for its induction via Nrf2. Taken together, our results indicate that the Nestin–Keap1–Nrf2 axis regulates cellular redox homeostasis and confers oxidative stress resistance in NSCLC.

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Histone deacetylase 3 preferentially binds and collaborates with the transcription factor RUNX1 to repress AML1–ETO–dependent transcription in t(8;21) AML

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.010707 ◽

2020 ◽

Vol 295 (13) ◽

pp. 4212-4223 ◽

Cited By ~ 1

Author(s):

Chun Guo ◽

Jian Li ◽

Nickolas Steinauer ◽

Madeline Wong ◽

Brent Wu ◽

...

Keyword(s):

Transcription Factor ◽

Fusion Protein ◽

Histone Deacetylase ◽

Transcriptional Activation ◽

Target Genes ◽

Chromosomal Translocation ◽

Histone Deacetylase 3 ◽

Genome Wide ◽

Related Transcription Factor ◽

Almost All

In up to 15% of acute myeloid leukemias (AMLs), a recurring chromosomal translocation, termed t(8;21), generates the AML1–eight–twenty-one (ETO) leukemia fusion protein, which contains the DNA-binding domain of Runt-related transcription factor 1 (RUNX1) and almost all of ETO. RUNX1 and the AML1–ETO fusion protein are coexpressed in t(8;21) AML cells and antagonize each other's gene-regulatory functions. AML1–ETO represses transcription of RUNX1 target genes by competitively displacing RUNX1 and recruiting corepressors such as histone deacetylase 3 (HDAC3). Recent studies have shown that AML1–ETO and RUNX1 co-occupy the binding sites of AML1–ETO–activated genes. How this joined binding allows RUNX1 to antagonize AML1–ETO–mediated transcriptional activation is unclear. Here we show that RUNX1 functions as a bona fide repressor of transcription activated by AML1–ETO. Mechanistically, we show that RUNX1 is a component of the HDAC3 corepressor complex and that HDAC3 preferentially binds to RUNX1 rather than to AML1–ETO in t(8;21) AML cells. Studying the regulation of interleukin-8 (IL8), a newly identified AML1–ETO–activated gene, we demonstrate that RUNX1 and HDAC3 collaboratively repress AML1–ETO–dependent transcription, a finding further supported by results of genome-wide analyses of AML1–ETO–activated genes. These and other results from the genome-wide studies also have important implications for the mechanistic understanding of gene-specific coactivator and corepressor functions across the AML1–ETO/RUNX1 cistrome.

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Genome-wide identification of novel long non-coding RNAs and their possible roles in hypoxic zebrafish brain

10.1101/2020.07.10.181842 ◽

2020 ◽

Author(s):

Bodhisattwa Banerjee ◽

Debaprasad Koner ◽

David Karasik ◽

Nirmalendu Saha

Keyword(s):

Target Genes ◽

Neuronal Development ◽

Rna Seq ◽

Master Regulators ◽

Expression Studies ◽

Genome Wide ◽

Development And Differentiation ◽

Non Coding Rnas ◽

Differentiation Pathways ◽

Syntenic Regions

AbstractLong non-coding RNAs (lncRNAs) are the master regulators of numerous biological processes. Hypoxia causes oxidative stress with severe and detrimental effects on brain function and acts as a critical initiating factor in the pathogenesis of Alzheimer’s disease (AD). From the RNA-Seq in the forebrain (Fb), midbrain (Mb), and hindbrain (Hb) regions of hypoxic and normoxic zebrafish, we identified novel lncRNAs, whose potential cis targets showed involvement in neuronal development and differentiation pathways. Under hypoxia, several lncRNAs and mRNAs were differentially expressed. Co-expression studies indicated that the Fb and Hb regions’ potential lncRNA target genes were involved in the AD pathogenesis. In contrast, those in Mb (cry1b, per1a, cipca) were responsible for regulating circadian rhythm. We identified specific lncRNAs present in the syntenic regions between zebrafish and humans, possibly functionally conserved. We thus identified several conserved lncRNAs as the probable regulators of AD genes (adrb3b, cav1, stat3, bace2, apoeb, psen1, s100b).

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