The CAF-1 complex couples Hippo pathway target gene expression and DNA replication

The Hippo signaling pathway regulates tissue growth and organ development in many animals, including humans. Pathway activity leads to inactivation of Yorkie (Yki), a transcriptional coactivator that drives expression of growth-promoting genes. In addition, Yki has been shown to recruit chromatin modifiers that enhance chromatin accessibility and thereby enhance Yki function. Here, we asked whether changes in chromatin accessibility that occur during DNA replication could also affect Yki function. We found that depletion of the chromatin assembly complex-1 (CAF-1) complex, a histone chaperone that is required for nucleosome assembly after DNA replication, in the wing imaginal epithelium leads to increased Hippo pathway target gene expression but does not affect expression of other genes. Yki shows greater association with target sites when CAF-1 is depleted and misregulation of target gene expression is Yki-dependent, suggesting that nucleosome assembly competes with Yki for pathway targets post-DNA replication. Consistent with this idea, increased target gene expression is DNA replication dependent and newly replicated chromatin at target sites shows marked nucleosome depletion when CAF-1 function is reduced. These observations suggest a connection between cell cycle progression and Hippo pathway target expression, providing insights into functions of the Hippo pathway in normal and abnormal tissue growth.

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Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00077.2014 ◽

2014 ◽

Vol 307 (2) ◽

pp. G196-G204 ◽

Cited By ~ 88

Author(s):

James L. Grijalva ◽

Megan Huizenga ◽

Kaly Mueller ◽

Steven Rodriguez ◽

Joseph Brazzo ◽

...

Keyword(s):

Gene Expression ◽

Body Weight ◽

Liver Regeneration ◽

Signaling Pathway ◽

Target Gene ◽

Hippo Pathway ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

Target Gene Expression ◽

The Hippo Pathway

The Hippo signaling pathway has been implicated in mammalian organ size regulation and tumor suppression. Specifically, the Hippo pathway plays a critical role regulating the activity of transcriptional coactivator Yes-associated protein (YAP), which modulates a proliferative transcriptional program. Recent investigations have demonstrated that while this pathway is activated in quiescent livers, its inhibition leads to liver overgrowth and tumorigenesis. However, the role of the Hippo pathway during the natural process of liver regeneration remains unknown. Here we investigated alterations in the Hippo signaling pathway and YAP activation during liver regeneration using a 70% partial hepatectomy (PH) rat model. Our results indicate an increase in YAP activation by 1 day following PH as demonstrated by increased YAP nuclear localization and increased YAP target gene expression. Investigation of the Hippo pathway revealed a decrease in the activation of core kinases Mst1/2 by 1 day as well as Lats1/2 and its adapter protein Mob1 by 3 days following PH. Evaluation of liver-to-body weight ratios indicated that the liver reaches its near normal size by 7 days following PH, which correlated with a return to baseline YAP nuclear levels and target gene expression. Additionally, when liver size was restored, Mst1/2 kinase activation returned to levels observed in quiescent livers indicating reactivation of the Hippo signaling pathway. These findings illustrate the dynamic changes in the Hippo signaling pathway and YAP activation during liver regeneration, which stabilize when the liver-to-body weight ratio reaches homeostatic levels.

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FLT3ITD Target Enhancers Are Primed but Inaccessible in Fetal Hematopoietic Progenitors

Blood ◽

10.1182/blood-2019-126201 ◽

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.

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SUMOylation regulates the protein network and chromatin accessibility at glucocorticoid receptor-binding sites

Nucleic Acids Research ◽

10.1093/nar/gkab032 ◽

2021 ◽

Author(s):

Ville Paakinaho ◽

Joanna K Lempiäinen ◽

Gianluca Sigismondo ◽

Einari A Niskanen ◽

Marjo Malinen ◽

...

Keyword(s):

Gene Expression ◽

Glucocorticoid Receptor ◽

Transcriptional Repression ◽

Target Gene ◽

Enzyme Inhibitor ◽

Chromatin Accessibility ◽

Protein Network ◽

Chromatin Binding ◽

Target Gene Expression ◽

Associated Proteins

Abstract Glucocorticoid receptor (GR) is an essential transcription factor (TF), controlling metabolism, development and immune responses. SUMOylation regulates chromatin occupancy and target gene expression of GR in a locus-selective manner, but the mechanism of regulation has remained elusive. Here, we identify the protein network around chromatin-bound GR by using selective isolation of chromatin-associated proteins and show that the network is affected by receptor SUMOylation, with several nuclear receptor coregulators and chromatin modifiers preferring interaction with SUMOylation-deficient GR and proteins implicated in transcriptional repression preferring interaction with SUMOylation-competent GR. This difference is reflected in our chromatin binding, chromatin accessibility and gene expression data, showing that the SUMOylation-deficient GR is more potent in binding and opening chromatin at glucocorticoid-regulated enhancers and inducing expression of target loci. Blockage of SUMOylation by a SUMO-activating enzyme inhibitor (ML-792) phenocopied to a large extent the consequences of GR SUMOylation deficiency on chromatin binding and target gene expression. Our results thus show that SUMOylation modulates the specificity of GR by regulating its chromatin protein network and accessibility at GR-bound enhancers. We speculate that many other SUMOylated TFs utilize a similar regulatory mechanism.

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A review: hippo signaling pathway promotes tumor invasion and metastasis by regulating target gene expression

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-021-03604-8 ◽

2021 ◽

Author(s):

Hong-Li Li ◽

Qian-Yu Li ◽

Min-Jie Jin ◽

Chao-Fan Lu ◽

Zhao-Yang Mu ◽

...

Keyword(s):

Gene Expression ◽

Signaling Pathway ◽

Tumor Invasion ◽

Target Gene ◽

Hippo Signaling ◽

Invasion And Metastasis ◽

Hippo Signaling Pathway ◽

Target Gene Expression

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

Diabetes ◽

10.2337/db20-2049-p ◽

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

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

Applied Microbiology and Biotechnology ◽

10.1007/s00253-021-11269-z ◽

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.

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