scholarly journals HASTER is a transcriptional stabilizer of HNF1A

2021 ◽  
Author(s):  
Anthony Beucher ◽  
Irene Miguel-Escalada ◽  
Diego Balboa Alonso ◽  
Matias G De Vas ◽  
Miguel Angel Maestro ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Transcription Factor ◽  
Negative Feedback ◽  
Regulatory Element ◽  
Open Chromatin ◽  
Negative Feedback Loops ◽  
Dependent Inhibition ◽  
Disease Relevance ◽  
Pioneer Transcription Factor ◽  
In Cis

The biological purpose and disease relevance of long noncoding RNAs (lncRNAs) is poorly understood. We examined HASTER, a lncRNA antisense to HNF1A. Haploinsufficient mutations in HNF1A, encoding a homeodomain transcription factor, cause diabetes mellitus. Using mouse and human models, we show that HASTER maintains HNF1A at cell-specific physiological concentrations through positive and negative feedback loops. Haster mutant pancreatic β cells thus showed variegated HNF1A overexpression or silencing, causing insulin-deficiency and diabetes. We demonstrate that the HASTER promoter acts in cis to prevent HNF1A overexpression and silencing, and link HASTER-dependent inhibition to local remodelling of 3D chromatin architecture. We further show that HASTER negative feedback ensures that HNF1A creates open chromatin at appropriate cell-specific genome regions. Our studies expose a cis-regulatory element that is unlike enhancers or silencers, and instead stabilizes expression levels of a pioneer transcription factor. They also show that disruption of a mammalian lncRNA can cause diabetes mellitus.

scholarly journals Creb5 establishes the competence for Prg4 expression in articular cartilage

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Cheng-Hai Zhang ◽  
Yao Gao ◽  
Unmesh Jadhav ◽  
Han-Hwa Hung ◽  
Kristina M. Holton ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Articular Cartilage ◽  
Articular Chondrocytes ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Open Chromatin ◽  
Chromatin Conformation ◽  
Deep Zone ◽  
Egfr Signaling ◽  
Superficial Zone

AbstractA hallmark of cells comprising the superficial zone of articular cartilage is their expression of lubricin, encoded by the Prg4 gene, that lubricates the joint and protects against the development of arthritis. Here, we identify Creb5 as a transcription factor that is specifically expressed in superficial zone articular chondrocytes and is required for TGF-β and EGFR signaling to induce Prg4 expression. Notably, forced expression of Creb5 in chondrocytes derived from the deep zone of the articular cartilage confers the competence for TGF-β and EGFR signals to induce Prg4 expression. Chromatin-IP and ATAC-Seq analyses have revealed that Creb5 directly binds to two Prg4 promoter-proximal regulatory elements, that display an open chromatin conformation specifically in superficial zone articular chondrocytes; and which work in combination with a more distal regulatory element to drive induction of Prg4 by TGF-β. Our results indicate that Creb5 is a critical regulator of Prg4/lubricin expression in the articular cartilage.

scholarly journals Creb5 establishes the competence for Prg4 expression in articular cartilage

2020 ◽  
Author(s):  
Cheng-Hai Zhang ◽  
Yao Gao ◽  
Unmesh Jadhav ◽  
Han-Hwa Hung ◽  
Kristina M Holton ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Articular Cartilage ◽  
Articular Chondrocytes ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Open Chromatin ◽  
Chromatin Conformation ◽  
Deep Zone ◽  
Egfr Signaling ◽  
Superficial Zone

AbstractA hallmark of cells comprising the superficial zone of articular cartilage is their expression of lubricin, encoded by the Prg4 gene, that lubricates the joint and protects against the development of arthritis. Here, we identify Creb5 as a transcription factor that is specifically expressed in superficial zone articular chondrocytes and is required for TGF-β and EGFR signaling to induce Prg4 expression. Notably, forced expression of Creb5 in chondrocytes derived from the deep zone of the articular cartilage confers the competence for TGF-β and EGFR signals to induce Prg4 expression. Chromatin-IP and ATAC-Seq analyses have revealed that Creb5 directly binds to two Prg4 promoter-proximal regulatory elements, that display an open chromatin conformation specifically in superficial zone articular chondrocytes; and which work in combination with a more distal regulatory element to drive induction of Prg4 by TGF-β. Our results indicate that Creb5 is a critical regulator of Prg4/lubricin expression in the articular cartilage.

scholarly journals Subtype-associated epigenomic landscape and 3D genome structure in bladder cancer

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Tejaswi Iyyanki ◽  
Baozhen Zhang ◽  
Qixuan Wang ◽  
Ye Hou ◽  
Qiushi Jin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Transcription Factor ◽  
Cancer Cell ◽  
Genome Structure ◽  
Transcription Factor Binding ◽  
Specific Gene ◽  
Open Chromatin ◽  
Factor Binding ◽  
3D Genome ◽  
Genome Wide

Abstract Muscle-invasive bladder cancers are characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. Transcriptionally, FOXA1, GATA3, and PPARG are shown to be essential for luminal subtype-specific gene regulation and subtype switching, while TP63, STAT3, and TFAP2 family members are critical for regulation of basal subtype-specific genes. Despite these advances, the underlying epigenetic mechanisms and 3D chromatin architecture responsible for subtype-specific regulation in bladder cancer remain unknown. Result We determine the genome-wide transcriptome, enhancer landscape, and transcription factor binding profiles of FOXA1 and GATA3 in luminal and basal subtypes of bladder cancer. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct transcription factor binding at distal enhancers of luminal and basal bladder cancers. Finally, we identify a novel clinically relevant transcription factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration. Conclusion In summary, our work identifies unique epigenomic signatures and 3D genome structures in luminal and basal urinary bladder cancers and suggests a novel link between the circadian transcription factor NPAS2 and a clinical bladder cancer subtype.

Transvection and Silencing of the Scr Homeotic Gene of Drosophila melanogaster

Genetics ◽  
2002 ◽  
Vol 161 (2) ◽  
pp. 733-746
Author(s):  
Jeffrey W Southworth ◽  
James A Kennison
Keyword(s):  
Drosophila Melanogaster ◽  
Chromosomal Aberrations ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Anomalous Behavior ◽  
Polycomb Group ◽  
Homeotic Gene ◽  
Polycomb Group Proteins ◽  
Sex Combs Reduced ◽  
In Cis

Abstract The Sex combs reduced (Scr) gene specifies the identities of the labial and first thoracic segments in Drosophila melanogaster. In imaginal cells, some Scr mutations allow cis-regulatory elements on one chromosome to stimulate expression of the promoter on the homolog, a phenomenon that was named transvection by Ed Lewis in 1954. Transvection at the Scr gene is blocked by rearrangements that disrupt pairing, but is zeste independent. Silencing of the Scr gene in the second and third thoracic segments, which requires the Polycomb group proteins, is disrupted by most chromosomal aberrations within the Scr gene. Some chromosomal aberrations completely derepress Scr even in the presence of normal levels of all Polycomb group proteins. On the basis of the pattern of chromosomal aberrations that disrupt Scr gene silencing, we propose a model in which two cis-regulatory elements interact to stabilize silencing of any promoter or cis-regulatory element physically between them. This model also explains the anomalous behavior of the Scx allele of the flanking homeotic gene, Antennapedia. This allele, which is associated with an insertion near the Antennapedia P1 promoter, inactivates the Antennapedia P1 and P2 promoters in cis and derepresses the Scr promoters both in cis and on the homologous chromosome.

scholarly journals EPEN-30. C11ORF95-RELA FUSION PROTEIN ENGAGES NOVEL GENOMIC LOCI TO DRIVE MURINE EPENDYMOMA GROWTH

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii314-iii314
Author(s):  
Amir Arabzade ◽  
Yanhua Zhao ◽  
Srinidhi Varadharajan ◽  
Hsiao-Chi Chen ◽  
Austin Stuckert ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Molecular Targets ◽  
Lead Target ◽  
Open Chromatin ◽  
Rna Seq ◽  
In Utero Electroporation ◽  
Pathway Activation ◽  
Mouse Cells ◽  
Shed Light

Abstract RATIONALE Over 70% of supratentorial (ST) ependymoma are characterized by an oncogenic fusion between C11ORF95 and RELA. C11ORF95-RELA fusion is frequently the sole genetic driver detected in ST ependymoma, thus ranking this genomic event as a lead target for therapeutic investigation. RELA is a transcription factor (TF) central to mediating NF-kB pathway activation in processes such as inflammation, cellular metabolism, and chemotaxis. HYPOTHESIS: We posited that C11ORF95-RELA acts as an oncogenic TF that aberrantly shapes the tumor epigenome to drive aberrant transcription. Approach: To this end we developed an in utero electroporation (IUE) mouse model of ependymoma to express C11ORF95-RELA during embryonic development. Our IUE approach allowed us to develop C11ORF95-RELA driven tumor models and cell lines. We comprehensively characterized the epigenome and transcriptome of C11ORF95-RELA fusion driven mouse cells by H3K27ac ChIP-seq, ATAC-seq, and RNA-seq. RESULTS This data revealed that: 1) C11ORF95-RELA directly engages ‘open’ chromatin and is enriched at regions with known RELA TF binding sites as well as novel genomic loci/motifs, 2) C11ORF95-RELA preferentially binds to both H3K27ac (active) enhancers and promoters, and 3) Bound C11ORF95-RELA promoter loci are associated with increased transcription of genes shared with human ependymoma. CONCLUSION Our findings shed light on the transcriptional mechanisms of C11ORF95-RELA, and reveal downstream targets that may represent cancer dependency genes and molecular targets.

Placental Accumulation of Triacylglycerols in Gestational Diabetes Mellitus and Its Association with Altered Fetal Growth are Related to the Differential Expressions of Proteins of Lipid Metabolism

2020 ◽  
Author(s):  
Manoharan Balachandiran ◽  
Zachariah Bobby ◽  
Gowri Dorairajan ◽  
Sajini Elizabeth Jacob ◽  
Victorraj Gladwin ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Fetal Growth ◽  
Fatty Acid Synthase ◽  
Regulatory Element ◽  
Acid Oxidation ◽  
Placental Proteins

Abstract Introduction Gestational diabetes mellitus (GDM) exhibit altered placental lipid metabolism. The molecular basis of this altered metabolism is not clear. Altered placental expression of proteins of lipogenesis and fatty acid oxidation may be involved in the placental accumulation of triacylglycerols (TG). The present study was aimed at investigating the differential expressions of placental proteins related to lipid metabolism among GDM women in comparison with control pregnant women (CPW) and to correlate them with maternal and fetal lipid parameters as well as altered fetal growth. Materials and Methods Maternal blood, cord blood, and placental samples were collected from GDM and CPW. The biochemical parameters, glucose, lipid profile and free fatty acids (FFA) were measured. The placental TG content was measured. Differential placental expressions of proteins; phosphatidylinositol-3-kinase (PI3K) p85α, PI3K p110α,liver X receptor alpha (LXRα), sterol regulatory element binding protein1(SREBP1), fatty acid synthase (FAS), stearyl CoA desaturase1 (SCD1), lipoprotein lipase (LPL),Peroxisome proliferator-activated receptor (PPAR)α and PPARγ were analysed by western blotting and immunohistochemistry. Results Placental protein expressions of PI3K p110α, LXRα, FAS, SCD1, and LPL were found to be significantly higher, whereas PPARα and PPARγ were lower in GDM women compared with CPW. The placental TG content and cord plasma FFA were increased in GDM women compared with CPW. The placental TG content positively correlated with Ponderal index of GDM new-borns. Conclusion Differential expressions of placental proteins related to lipid metabolism in GDM might have led to placental TG accumulation. This might have contributed to the fetal overgrowth in GDM.

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