Gene regulation through chromatin remodelling by members of the nuclear receptor superfamily

2000 ◽  
Vol 28 (4) ◽  
pp. 369-373 ◽  
Author(s):  
I. J. McEwan
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Transcription Factors ◽  
Thyroid Hormones ◽  
Target Gene ◽  
Protein Complexes ◽  
Nuclear Receptor Superfamily ◽  
Target Gene Expression ◽  
Dna Elements ◽  
Introductory Review

The intracellular receptors for steroid hormones, thyroid hormones, retinoids and vitamin D3 are known to bind to specific DNA elements and thus regulate target gene expression. This introductory review and the following papers address some of the mechanisms underlying this action. In particular, the ability of this family of transcription factors to recruit multi-protein complexes that have the capacity to remodel chromatin structure in order to silence or activate target gene expression is discussed.

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 pVHL regulates protein stability of TCF/LEF transcription factor family via ubiquitin-independent proteasomal degradation

2021 ◽  
Author(s):  
Caixia Wang ◽  
Xiaozhi Rong ◽  
Haifeng Zhang ◽  
Bo Wang ◽  
Yan Bai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Protein Stability ◽  
Ubiquitin Ligase ◽  
Target Gene ◽  
E3 Ubiquitin Ligase ◽  
Proteasomal Degradation ◽  
26S Proteasome ◽  
Cell Fate Decisions ◽  
Target Gene Expression

The Wnt/β-catenin signaling pathway plays key roles in development and adult tissue homeostasis by controlling cell proliferation and cell fate decisions. In this pathway, transcription factors TCF/LEFs are the key components to repress target gene expression by recruiting co-repressors or to activate target gene expression by recruiting β-catenin when the Wnt signals are absent or present, respectively. While progress has been made in our understanding of Wnt signaling regulation, the underlying mechanism that regulates the protein stability of the TCF/LEF family is far less clear. Here, we show that von Hippel-Lindau protein (pVHL), which is the substrate recognition component in an E3 ubiquitin ligase complex, controls TCF/LEF protein stability. Unexpectedly, pVHL directly binds to TCF/LEFs and promotes their proteasomal degradation independent of E3 ubiquitin ligase activity. Knockout of vhl in zebrafish embryos leads to a reduction of dorsal habenular neurons and this effect is upstream of dorsal habenular neurons phenotype in tcf7l2-null mutants. Our study uncovers a previously unknown mechanism for the protein stability regulation of the TCF/LEF transcription factors and demonstrates that pVHL contains a 26S proteasome binding domain that drives ubiquitin-independent proteasomal degradation. These findings provide new insights into the ubiquitin-independent actions of pVHL and uncover novel mechanistical regulation of Wnt/β-catenin signaling.

scholarly journals Endogenous BioID elucidates TCF7L1 interactome modulation upon GSK-3 inhibition in mouse ESCs

2018 ◽  
Author(s):  
Steven Moreira ◽  
Caleb Seo ◽  
Victor Gordon ◽  
Sansi Xing ◽  
Ruilin Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Transcription Factors ◽  
Target Gene ◽  
Single Copy ◽  
List Type ◽  
Interacting Proteins ◽  
Mouse Escs ◽  
Biotin Ligase ◽  
Biotin Labeling

Modulation of Wnt target gene expression via the TCF/LEFs remains poorly understood. We employ proximity-based biotin labeling (BioID) to examine GSK-3 inhibitor effects on the TCF7L1 interactome in mouse ESCs. We generated ESC lines with biotin ligase BirA* fused to TCF7L1 by knocking it into the endogenous TCF7L1 locus or by inserting a doxinducible BirA*-TCF7L1 transgene into the Rosa26 locus. Induction yielded BirA*-TCF7L1 levels 3-fold higher than in the endogenous system, but substantial overlap in biotinylated proteins with high peptide counts were detected by each method. Known TCF7L1 interactors TLE3/4 and β-catenin, and numerous proteins not previously associated with TCF7L1, were identified in both systems. Despite reduced BirA*-TCF7L1 levels, the number of hits identified with both BioID approaches increased after GSK-3 inhibition. We elucidate the network of TCF7L1 proximal proteins regulated by GSK-3 inhibition, validate the utility of endogenous BioID, and provide mechanistic insights into TCF7L1 target gene regulation.HighlightsBirA*-TCF7L1 at single-copy physiological levels generates robust BioID dataCHIR99021 reduces TCF7L1 levels but increases detectable TCF7L1-proximal proteinsThe TCF7L1 interactome of largely epigenetic/transcription factors fluctuates with GSK-3 inhibitionJMJD1C, SALL4 and BRG1/SMARCA4 are validated as TCF7L-interacting proteins

Nuclear hormone receptors PXR and CAR and metabolic diseases

2014 ◽  
Vol 19 (2) ◽  
Author(s):  
Li Mo ◽  
Jinhan He
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Thyroid Hormones ◽  
Nuclear Receptors ◽  
Target Gene ◽  
Hormone Receptors ◽  
Metabolic Diseases ◽  
Gene Promoters ◽  
Response Elements ◽  
Lipid Metabolites

AbstractNuclear receptors (NRs) belong to a superfamily of evolutionarily related DNA-binding transcription factors that can be activated by steroid and thyroid hormones, and other lipid metabolites. Ligand activated NRs can regulate target gene expression by binding to DNA response elements present in the target gene promoters. Through this regulation, NRs are broadly implicated in physiology and metabolism. In this chapter, we will focus on the xenobiotic receptors and their recently discovered functions in metabolic diseases.

scholarly journals MADS Domain Transcription Factors Mediate Short-Range DNA Looping That Is Essential for Target Gene Expression in Arabidopsis

2013 ◽  
Vol 25 (7) ◽  
pp. 2560-2572 ◽  
Author(s):  
M. A. Mendes ◽  
R. F. Guerra ◽  
M. C. Berns ◽  
C. Manzo ◽  
S. Masiero ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Short Range ◽  
Target Gene ◽  
Dna Looping ◽  
Target Gene Expression

2049-P: The Chd4 Helicase of the Nucleosome Remodeling and Deacetylase Complex Modulates Pdx1 Target Gene Expression In Vitro

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 2049-P
Author(s):  
REBECCA K. DAVIDSON ◽  
NOLAN CASEY ◽  
JASON SPAETH
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Nucleosome Remodeling ◽  
Target Gene Expression

scholarly journals The AML-associated K313 mutation enhances C/EBPα activity by leading to C/EBPα overexpression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Ian Edward Gentle ◽  
Isabel Moelter ◽  
Mohamed Tarek Badr ◽  
Konstanze Döhner ◽  
Michael Lübbert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Culture ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Transcriptional Activity ◽  
Target Gene ◽  
Wild Type ◽  
Elevated Expression ◽  
Factor C ◽  
Acute Myeloid

AbstractMutations in the transcription factor C/EBPα are found in ~10% of all acute myeloid leukaemia (AML) cases but the contribution of these mutations to leukemogenesis is incompletely understood. We here use a mouse model of granulocyte progenitors expressing conditionally active HoxB8 to assess the cell biological and molecular activity of C/EBPα-mutations associated with human AML. Both N-terminal truncation and C-terminal AML-associated mutations of C/EBPα substantially altered differentiation of progenitors into mature neutrophils in cell culture. Closer analysis of the C/EBPα-K313-duplication showed expansion and prolonged survival of mutant C/EBPα-expressing granulocytes following adoptive transfer into mice. C/EBPα-protein containing the K313-mutation further showed strongly enhanced transcriptional activity compared with the wild-type protein at certain promoters. Analysis of differentially regulated genes in cells overexpressing C/EBPα-K313 indicates a strong correlation with genes regulated by C/EBPα. Analysis of transcription factor enrichment in the differentially regulated genes indicated a strong reliance of SPI1/PU.1, suggesting that despite reduced DNA binding, C/EBPα-K313 is active in regulating target gene expression and acts largely through a network of other transcription factors. Strikingly, the K313 mutation caused strongly elevated expression of C/EBPα-protein, which could also be seen in primary K313 mutated AML blasts, explaining the enhanced C/EBPα activity in K313-expressing cells.

scholarly journals On the way toward regulatable expression systems in acetic acid bacteria: target gene expression and use cases

2021 ◽  
Author(s):  
Philipp Moritz Fricke ◽  
Angelika Klemm ◽  
Michael Bott ◽  
Tino Polen
Keyword(s):  
Gene Expression ◽  
Acetic Acid ◽  
Literature Search ◽  
Target Gene ◽  
Target Genes ◽  
Recombinant Dna ◽  
Acetic Acid Bacteria ◽  
Homoserine Lactone ◽  
Expression Systems ◽  
Target Gene Expression

Abstract Acetic acid bacteria (AAB) are valuable biocatalysts for which there is growing interest in understanding their basics including physiology and biochemistry. This is accompanied by growing demands for metabolic engineering of AAB to take advantage of their properties and to improve their biomanufacturing efficiencies. Controlled expression of target genes is key to fundamental and applied microbiological research. In order to get an overview of expression systems and their applications in AAB, we carried out a comprehensive literature search using the Web of Science Core Collection database. The Acetobacteraceae family currently comprises 49 genera. We found overall 6097 publications related to one or more AAB genera since 1973, when the first successful recombinant DNA experiments in Escherichia coli have been published. The use of plasmids in AAB began in 1985 and till today was reported for only nine out of the 49 AAB genera currently described. We found at least five major expression plasmid lineages and a multitude of further expression plasmids, almost all enabling only constitutive target gene expression. Only recently, two regulatable expression systems became available for AAB, an N-acyl homoserine lactone (AHL)-inducible system for Komagataeibacter rhaeticus and an l-arabinose-inducible system for Gluconobacter oxydans. Thus, after 35 years of constitutive target gene expression in AAB, we now have the first regulatable expression systems for AAB in hand and further regulatable expression systems for AAB can be expected. Key points • Literature search revealed developments and usage of expression systems in AAB. • Only recently 2 regulatable plasmid systems became available for only 2 AAB genera. • Further regulatable expression systems for AAB are in sight.

Inhibition of prostate cancer growth by vitamin D: Regulation of target gene expression

2002 ◽  
Vol 88 (2) ◽  
pp. 363-371 ◽  
Author(s):  
Aruna V. Krishnan ◽  
Donna M. Peehl ◽  
David Feldman
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Vitamin D ◽  
Target Gene ◽  
Cancer Growth ◽  
Target Gene Expression
Sign in / Sign up

Export Citation Format

Share Document