scholarly journals BET Proteins Regulate Expression of Osr1 in Early Kidney Development

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1878
Author(s):  
Janina Schreiber ◽  
Nastassia Liaukouskaya ◽  
Lars Fuhrmann ◽  
Alexander-Thomas Hauser ◽  
Manfred Jung ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progenitor Cell ◽  
Kidney Development ◽  
Gene Activation ◽  
Renal Development ◽  
Prenatal Programming ◽  
Bet Inhibitor ◽  
Bet Inhibitors ◽  
Nephron Progenitor

In utero renal development is subject to maternal metabolic and environmental influences affecting long-term renal function and the risk of developing chronic kidney failure and cardiovascular disease. Epigenetic processes have been implicated in the orchestration of renal development and prenatal programming of nephron number. However, the role of many epigenetic modifiers for kidney development is still unclear. Bromodomain and extra-terminal domain (BET) proteins act as histone acetylation reader molecules and promote gene transcription. BET family members Brd2, Brd3 and Brd4 are expressed in the nephrogenic zone during kidney development. Here, the effect of the BET inhibitor JQ1 on renal development is evaluated. Inhibition of BET proteins via JQ1 leads to reduced growth of metanephric kidney cultures, loss of the nephron progenitor cell population, and premature and disturbed nephron differentiation. Gene expression of key nephron progenitor transcription factor Osr1 is downregulated after 24 h BET inhibition, while Lhx1 and Pax8 expression is increased. Mining of BRD4 ChIP-seq and gene expression data identify Osr1 as a key factor regulated by BRD4-controlled gene activation. Inhibition of BRD4 by BET inhibitor JQ1 leads to downregulation of Osr1, thereby causing a disturbance in the balance of nephron progenitor cell self-renewal and premature differentiation of the nephron, which ultimately leads to kidney hypoplasia and disturbed nephron development. This raises questions about the potential teratogenic effects of BET inhibitors for embryonic development. In summary, our work highlights the role of BET proteins for prenatal programming of nephrogenesis and identifies Osr1 as a potential target of BET proteins.

scholarly journals Kidney‐in‐a‐lymph node: A novel organogenesis assay to model human renal development and test nephron progenitor cell fates

2019 ◽  
Vol 13 (9) ◽  
pp. 1724-1731 ◽  
Author(s):  
Maria Giovanna Francipane ◽  
Bing Han ◽  
Leif Oxburgh ◽  
Sunder Sims‐Lucas ◽  
Zhongwei Li ◽  
...  
Keyword(s):  
Lymph Node ◽  
Progenitor Cell ◽  
Renal Development ◽  
Cell Fates ◽  
Nephron Progenitor

scholarly journals Wnt signaling in kidney: the initiator or terminator?

2020 ◽  
Vol 98 (11) ◽  
pp. 1511-1523 ◽  
Author(s):  
Ping Meng ◽  
Mingsheng Zhu ◽  
Xian Ling ◽  
Lili Zhou
Keyword(s):  
Cell Differentiation ◽  
Embryonic Development ◽  
Wnt Signaling ◽  
Tissue Repair ◽  
Progenitor Cell ◽  
Kidney Development ◽  
Kidney Diseases ◽  
Electrolyte Balance ◽  
Tissue Repair And Regeneration

Abstract The kidney is a key organ in the human body that excretes toxins and sustains the water–electrolyte balance. During embryonic development and disease progression, the kidney undergoes enormous changes in macrostructure, accompanied by a variety of microstructural histological changes, such as glomerular formation and sclerosis, tubule elongation and atrophy, interstitial establishment, and fibrosis progression. All of these rely on the frequent occurrence of cell death and growth. Notably, to overcome disease, some cells regenerate through self-repair or progenitor cell differentiation. However, the signaling mechanisms underlying kidney development and regeneration have not been elucidated. Recently, Wnt signaling has been noted to play an important role. Although it is a well-known developmental signal, the role of Wnt signaling in kidney development and regeneration is not well recognized. In this review, we review the role of Wnt signaling in kidney embryonic development, tissue repair, cell division, and progenitor cell differentiation after injury. Moreover, we briefly highlight advances in our understanding of the pathogenic mechanisms of Wnt signaling in mediating cellular senescence in kidney parenchymal and stem cells, an irreversible arrest of cell proliferation blocking tissue repair and regeneration. We also highlight the therapeutic targets of Wnt signaling in kidney diseases and provide important clues for clinical strategies.

scholarly journals MOZ and BMI1 play opposing roles during Hox gene activation in ES cells and in body segment identity specification in vivo

2015 ◽  
Vol 112 (17) ◽  
pp. 5437-5442 ◽  
Author(s):  
Bilal N. Sheikh ◽  
Natalie L. Downer ◽  
Belinda Phipson ◽  
Hannah K. Vanyai ◽  
Andrew J. Kueh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Es Cells ◽  
Gene Activation ◽  
Embryonic Stem ◽  
Mrna Levels ◽  
Body Segment ◽  
Initial Activation ◽  
Activation Phase

Hox genes underlie the specification of body segment identity in the anterior–posterior axis. They are activated during gastrulation and undergo a dynamic shift from a transcriptionally repressed to an active chromatin state in a sequence that reflects their chromosomal location. Nevertheless, the precise role of chromatin modifying complexes during the initial activation phase remains unclear. In the current study, we examined the role of chromatin regulators during Hox gene activation. Using embryonic stem cell lines lacking the transcriptional activator MOZ and the polycomb-family repressor BMI1, we showed that MOZ and BMI1, respectively, promoted and repressed Hox genes during the shift from the transcriptionally repressed to the active state. Strikingly however, MOZ but not BMI1 was required to regulate Hox mRNA levels after the initial activation phase. To determine the interaction of MOZ and BMI1 in vivo, we interrogated their role in regulating Hox genes and body segment identity using Moz;Bmi1 double deficient mice. We found that the homeotic transformations and shifts in Hox gene expression boundaries observed in single Moz and Bmi1 mutant mice were rescued to a wild type identity in Moz;Bmi1 double knockout animals. Together, our findings establish that MOZ and BMI1 play opposing roles during the onset of Hox gene expression in the ES cell model and during body segment identity specification in vivo. We propose that chromatin-modifying complexes have a previously unappreciated role during the initiation phase of Hox gene expression, which is critical for the correct specification of body segment identity.

scholarly journals Ldb1 mediates trans enhancement in mammals

2018 ◽  
Author(s):  
K. Monahan ◽  
A. Horta ◽  
A.M. Mumbay-Wafula ◽  
L. Li ◽  
Y. Zhao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Olfactory Receptor ◽  
Essential Role ◽  
Gene Activation ◽  
Lim Domain ◽  
Transcriptional Enhancers ◽  
Dna Motif ◽  
Or Gene ◽  
Greek Island

AbstractSingular olfactory receptor (OR) gene expression1,2 coincides with the formation of a multi-chromosomal enhancer hub that associates with the only transcribed OR allele in each cell3,4. This hub consists of converging transcriptional enhancers3, or “Greek Islands”, defined by stereotypic binding of Lhx2 and Ebf on a shared, composite DNA motif5. How this multi-chromosomal hub, or any other genomic compartment, assembles is unknown, and so is the significance of compartmentalization in transcription. Here, we report that LIM domain binding protein 1 (Ldb1), which is recruited by Lhx2 and Ebf to Greek Islands, promotes robust and specific trans interactions between these enhancers. In addition to disrupting Greek Island hubs, Ldb1 deletion also causes significant downregulation of OR transcription. Thus, our data provide insight to the formation of genomic compartments, confirm the essential role of interchromosomal interactions in OR gene choice, and establish trans enhancement as a mechanism for mammalian gene activation.

Role of microRNAs in Renal Parenchymal Diseases—A New Dimension

2018 ◽  
Author(s):  
Saeed Kamran Shaffi ◽  
David Galas ◽  
Alton Etheridge ◽  
Christos Argyropoulos
Keyword(s):  
Gene Expression ◽  
Normal Development ◽  
Therapeutic Targets ◽  
Therapeutic Agents ◽  
Renal Development ◽  
Renal Repair ◽  
Eukaryotic Organisms

Since their discovery in 1993, numerous microRNAs (miRNAs) have been identified in humans and other eukaryotic organisms, and their role as key regulators of gene expression is still being elucidated. It is now known that miRNAs not only play a central role in the processes that ensure normal development and physiology, but they are often dysregulated in various diseases. In this review, we present an overview of the role of miRNAs in normal renal development and physiology, in maladaptive renal repair after injury, and in the pathogenesis of renal parenchymal diseases. In addition, we describe methods used for their detection and their potential as therapeutic targets. Continued research on renal miRNAs will undoubtedly improve our understanding of diseases affecting the kidneys and may also lead to new therapeutic agents.

scholarly journals FT-1101: A Structurally Distinct Pan-BET Bromodomain Inhibitor with Activity in Preclinical Models of Hematologic Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1367-1367 ◽  
Author(s):  
David S Millan ◽  
Monica A Alvarez Morales ◽  
Kenneth J Barr ◽  
Daniel Cardillo ◽  
Alan Collis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Proliferative Activity ◽  
Xenograft Model ◽  
Hematologic Malignancies ◽  
In Vivo Efficacy ◽  
Bet Inhibitor ◽  
Super Enhancer ◽  
Bet Inhibitors ◽  
Myc Gene

Abstract Members of the Bromodomain and Extra-Terminal (BET) family of bromodomain-containing proteins (BRD2, BRD3, BRD4, and BRDT) bind to acetylated lysine residues on histone tails and act as epigenetic readers to regulate chromatin structure and gene expression. In particular, BET family member BRD4 has been shown to positively regulate the expression of MYC and other critical cancer-associated genes through the localization of BRD4 to super-enhancer regulatory elements. Results from preclinical studies conducted using the small molecule tool BET inhibitor (+)-JQ1, and emerging data from clinical trials of BET inhibitors in leukemia and lymphoma patients, have provided support for the therapeutic potential of BET inhibitors in hematologic malignancies. A protein structure-guided drug design approach was employed to explore small molecule acetyl lysine mimetics and led to the identification of the BET inhibitor FT-1101, which is structurally unrelated to reported clinical-stage BET inhibitors in the (+)-JQ1 class. In biochemical binding assays, FT-1101 displayed equipotent inhibition of binding of both bromodomains in all four BET family members to a known bromodomain ligand (Kd ≤ 20 nM). In vitro, FT-1101 displayed potent anti-proliferative activity across a broad panel of human leukemia, lymphoma, and multiple myeloma cell lines, with 66 out of 123 cell lines having IC50 values < 500 nM. For the MV-4-11 acute myeloid leukemia cell line, the anti-proliferative activity of FT-1101 (IC50 = 40 nM) correlated with down-regulation of MYC gene and protein expression, suggesting that its anti-proliferative activity was at least in part due to suppression of MYC. Additionally, genome-wide mapping of BRD4 super-enhancer binding sites in MV-4-11 cells by ChIP-sequencing identified several potential pharmacodynamic biomarkers outside of the MYC signaling network. In vivo, in the MV-4-11 xenograft model, oral treatment with FT-1101 at its maximum tolerated dose resulted in significant tumor growth inhibition, including tumor regressions, on schedules ranging from once daily to once weekly, and similar activity was also observed in the THP-1 AML xenograft model. Superior in vivo efficacy in the MV-4-11 model was observed for FT-1101 relative to BET inhibitors of the (+)-JQ1 class. In vivo efficacy was associated with prolonged drug exposure and a >75% decrease in MYC gene expression in tumors that was sustained for at least 12 hours. FT-1101 also crossed the blood-brain barrier in mice, achieving a pharmacologically relevant free drug concentration in the brain. The promising preclinical profile of FT-1101 warranted its rapid progression into human clinical trials, and a Phase 1 study in patients with relapsed refractory acute leukemia or high-risk myelodysplastic syndrome is currently underway. Disclosures No relevant conflicts of interest to declare.

scholarly journals TET2 Loss Dysregulates the Behavior of Mesenchymal Stem Cells and Increases Their Ability to Promote TET2−/−-Driven Myeloid Malignancy Progression

2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 222s-222s
Author(s):  
Z. Zhao
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Progenitor Cell ◽  
Conditional Knockout ◽  
Hematopoietic Progenitor Cell ◽  
Bone Marrow Niche ◽  
Myeloid Malignancies

Background: TET2 is a methylcytosine dioxygenase that regulates cytosine hydroxymethylation. Although there are extensive data implicating a pivotal role of TET2 in hematopoietic stem/progenitor cell (HSPCs), the importance of TET2 in bone marrow mesenchymal stromal cells (BMSCs) remains unknown. Aim: Tet2 loss may dysregulate the integrity of bone marrow niche, by which affects the malignant progression. Methods: Generation and maintenance of Tet2 conditional knockout MiceAnalysis of 5-hmC and 5-mC levels using dot blotFlow cytometry analysis, cell sorting, and hematopoietic progenitor cell (HPC) assayMSC Culture and long-term coculture with HSPCsReal-time PCR and RAN-Seq AnalysisMeDIP-seq to profile the genome-wide distribution of 5hmC. Results: Here, we show that while both Tet2 f/f ;Mx1Cre (conditional Tet2-inactivation in hematopoietic cells) and Tet2 f/f ;MxfCre (germ line Tet2-inactivation) developed myeloid malignancies in mice, Tet2 f/f ;MxfCre mice had a significantly shortened survival compared with Tet2 f/f ;Mx1Cre mice. Interestingly, Tet2 −/− recipient mice exhibited a higher incident of myeloid malignancies and a significantly reduced survival rate compare with WT recipient mice. These data indicate that Tet2 −/− bone marrow niche might promote the progression of myeloid malignancies in Tet2 −/− mice. Strikingly, deletion of Tet2 in mesenchymal stem cells (MSCs) using Prx1-cre is associated with a significantly accelerated malignancy progression and shortened survival, suggesting that MSCs are the cell components in Tet2 −/− mice play a role in the initiation/progression of Tet2 −/−-driven myeloid malignancies. Furthermore, Tet2 −/− MSCs displayed a significantly increased self-renewal, proliferating and differentiation capability as assayed by the frequency of CFU-F and commitment toward osteoblasts. In addition, Tet2 −/− but not WT MSCs exhibited a significantly increased supportive capacity to Tet2 −/− HSC/HPC proliferation. RNA-sequencing analysis revealed that Tet2 −/− MSCs exhibited a distinct gene expression profiles with 468 dysregulated genes as compared with WT MSCs. Furthermore, the number of 5-hmC peaks were significantly decreased in Tet2 −/− MSCs compared with WT MSCs based on whole genomic 5-hmC profiling. The majority of TET2-dependent 5hmC modifications in MSCs are located within genes. We then examined TET2 gene expression in MSCs derived from human myeloproliferative neoplasms (MPN) patients and healthy individuals and found that TET2 and 5-hmC was moderately down-regulated in MPN MSCs as compared with healthy controls. Conclusion: These results highlight the critical role of TET2 in the maintenance of BMSC functions and osteoblast differentiation, and provide evidence that dysregulation of epigenetic modifier in BMSCs contributes to the progression of myeloid malignancies.

Stromal cells mediate retinoid-dependent functions essential for renal development

Development ◽  
1999 ◽  
Vol 126 (6) ◽  
pp. 1139-1148 ◽  
Author(s):  
C. Mendelsohn ◽  
E. Batourina ◽  
S. Fung ◽  
T. Gilbert ◽  
J. Dodd
Keyword(s):  
Vitamin A ◽  
Stromal Cells ◽  
Renal Cell ◽  
Kidney Development ◽  
Collecting Duct ◽  
Cell Types ◽  
Renal Development ◽  
Ureteric Bud ◽  
Renal Malformations

The essential role of vitamin A and its metabolites, retinoids, in kidney development has been demonstrated in vitamin A deficiency and gene targeting studies. Retinoids signal via nuclear transcription factors belonging to the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families. Inactivation of RARaplpha and RARbeta2 receptors together, but not singly, resulted in renal malformations, suggesting that within a given renal cell type, their concerted function is required for renal morphogenesis. At birth, RARalpha beta2(−) mutants displayed small kidneys, containing few ureteric bud branches, reduced numbers of nephrons and lacking the nephrogenic zone where new nephrons are continuously added. These observations have prompted us to investigate the role of RARalpha and RARbeta2 in renal development in detail. We have found that within the embryonic kidney, RARalpha and RARbeta2 are colocalized in stromal cells, but not in other renal cell types, suggesting that stromal cells mediate retinoid-dependent functions essential for renal development. Analysis of RARalpha beta2(−) mutant kidneys at embryonic stages revealed that nephrons were formed and revealed no changes in the intensity or distribution of molecular markers specific for different metanephric mesenchymal cell types. In contrast the development of the collecting duct system was greatly impaired in RARalpha beta2(−) mutant kidneys. Fewer ureteric bud branches were present, and ureteric bud ends were positioned abnormally, at a distance from the renal capsule. Analysis of genes important for ureteric bud morphogenesis revealed that the proto-oncogene c-ret was downregulated. Our results suggest that RARalpha and RARbeta2 are required for generating stromal cell signals that maintain c-ret expression in the embryonic kidney. Since c-ret signaling is required for ureteric bud morphogenesis, loss of c-ret expression is a likely cause of impaired ureteric bud branching in RARalpha beta2(−) mutants.

Chromatin Remodelers Interact with Eya1 and Six2 to Target Enhancers to Control Nephron Progenitor Cell Maintenance

2021 ◽  
Vol 32 (11) ◽  
pp. 2815-2833
Author(s):  
Jun Li ◽  
Jinshu Xu ◽  
Huihui Jiang ◽  
Ting Zhang ◽  
Aarthi Ramakrishnan ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Kidney Development ◽  
Regulatory Elements ◽  
Proximal Promoter ◽  
Specific Expression ◽  
Self Renewal ◽  
Content Type ◽  
Nephron Progenitors ◽  
Genome Wide ◽  
Nephron Progenitor

BackgroundEya1 is a critical regulator of nephron progenitor cell specification and interacts with Six2 to promote NPC self-renewal. Haploinsufficiency of these genes causes kidney hypoplasia. However, how the Eya1-centered network operates remains unknown.MethodsWe engineered a 2×HA-3×Flag-Eya1 knock-in mouse line and performed coimmunoprecipitation with anti-HA or -Flag to precipitate the multitagged-Eya1 and its associated proteins. Loss-of-function, transcriptome profiling, and genome-wide binding analyses for Eya1's interacting chromatin-remodeling ATPase Brg1 were carried out. We assayed the activity of the cis-regulatory elements co-occupied by Brg1/Six2 in vivo.ResultsEya1 and Six2 interact with the Brg1-based SWI/SNF complex during kidney development. Knockout of Brg1 results in failure of metanephric mesenchyme formation and depletion of nephron progenitors, which has been linked to loss of Eya1 expression. Transcriptional profiling shows conspicuous downregulation of important regulators for nephrogenesis in Brg1-deficient cells, including Lin28, Pbx1, and Dchs1-Fat4 signaling, but upregulation of podocyte lineage, oncogenic, and cell death–inducing genes, many of which Brg1 targets. Genome-wide binding analysis identifies Brg1 occupancy to a distal enhancer of Eya1 that drives nephron progenitor–specific expression. We demonstrate that Brg1 enrichment to two distal intronic enhancers of Pbx1 and a proximal promoter region of Mycn requires Six2 activity and that these Brg1/Six2-bound enhancers govern nephron progenitor–specific expression in response to Six2 activity.ConclusionsOur results reveal an essential role for Brg1, its downstream pathways, and its interaction with Eya1-Six2 in mediating the fine balance among the self-renewal, differentiation, and survival of nephron progenitors.

Prenatal programming of obesity in a swine model of leptin resistance: modulatory effects of controlled postnatal nutrition and exercise

2014 ◽  
Vol 5 (3) ◽  
pp. 248-258 ◽  
Author(s):  
A. Barbero ◽  
S. Astiz ◽  
C. Ovilo ◽  
C. J. Lopez-Bote ◽  
M. L. Perez-Solana ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Patterns ◽  
Muscle Growth ◽  
Leptin Resistance ◽  
Control Group ◽  
Swine Model ◽  
Main Role ◽  
Prenatal Programming ◽  
Prenatal Malnutrition

The main role of early nutritional programming in the current rise of obesity and associated diseases is well known. However, translational studies are mostly based in postnatal food excess and, thus, there is a paucity of information on the phenotype of individuals with prenatal deficiencies but adequate postnatal conditions. Thus, we assessed the effects of prenatal programming (comparing descendants from females fed with a diet fulfilling 100 or only 50% of their nutritional requirements for pregnancy) on gene expression, patterns of growth and fattening, metabolic status and puberty attainment of a swine model of obesity/leptin resistance with controlled postnatal nutrition and opportunity of exercise. Maternal restriction was related to changes in the relationships among gene expression of positive (insulin-like growth factors 1 and 2) and negative (myostatin) regulators of muscle growth, with negative correlations in gilts from restricted pregnancies and positive relationships in the control group. In spite of these differences, the patterns of growth and fattening and the metabolic features during juvenile growth were similar in control gilts and gilts from restricted pregnancies. Concomitantly, there was a lack of differences in the timing of puberty attainment. However, after reaching puberty and adulthood, females from restricted pregnancies were heavier and more corpulent than control gilts, though such increases in weight and size were not accompanied by increases in adiposity. In conclusion, in spite of changes in gene expression induced by developmental programming, the propensity for higher weight and adiposity of individuals exposed to prenatal malnutrition may be modulated by controlled food intake and opportunity of physical exercise during infant and juvenile development.

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