Global change of RNA expression upon silencing TET1 in PDX2 B-ALL cells; Landscapes of TET1 and STAT5B binding on DNA across the entire genome in PDX2 B-ALL cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE190853 | GEO | 2023/02/13
REPOSITORIES: GEO
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Project description:Here we report both TET1-WT and catalytically dead mutant TET1 (TET1-MUT) directly interact with STAT5B in PDX2 B-ALL cells. To study the landscape of TET1 and STAT5B binding in whole genomic DNA and test if the STAT5B binding signal is affected by TET1, we conduct the ChIP-seq assay with flag antibody (TET1-WT, TET1-MUT) and STAT5B antibody (sgNS or sgTET1) respectively. The results showed that TET1 bound peaks overlap with STAT5B very well and the tag density of STAT5B on target genes decreases in TET1-impeded cells. We conclude that TET1 recruit STAT5B to the promoters of its target genes and further promote the target genes’ transcriptions.
2023-02-13 | GSE190852 | GEO
Project description:Global change of RNA expression upon silencing TET1 in PDX2 B-ALL cells Landscapes of TET1 and STAT5B binding on DNA across the entire genome in PDX2 B-ALL cells
| PRJNA788624 | ENA
Project description:Here we report that TET1 has a critical role in B-ALL development. TET1-depleted cells delayed the onset of B-ALL. To investigate the mechanisms, we first generate the patient-derived xenograft cells (PDX2) and transduce with inducible-Cas9 and sgRNA targeting TET1. After treatment with doxycycline, we observe the expression of Cas9 and a depletion of TET1 protein. By using the high throughput sequencing RNA-seq, we check the potential targets of TET1 in B-ALL cells. Finally, we validate that CD72 and JCHAIN are two essential targets of TET1 signaling in B-ALL cells.
2023-02-13 | GSE190851 | GEO
Project description:Global change of RNA expression upon silencing TET1 in PDX2 B-ALL cells
| PRJNA788631 | ENA
Project description:Landscapes of TET1 and STAT5B binding on DNA across the entire genome in PDX2 B-ALL cells
| PRJNA788630 | ENA
Project description:BACKGROUND:DNA methylation is a heritable epigenetic mark, enabling stable but reversible gene repression. In mammalian cells, DNA methyltransferases (DNMTs) are responsible for modifying cytosine to 5-methylcytosine (5mC), which can be further oxidized by the TET dioxygenases to ultimately cause DNA demethylation. However, the genome-wide cooperation and functions of these two families of proteins, especially at large under-methylated regions, called canyons, remain largely unknown. RESULTS:Here we demonstrate that DNMT3A and TET1 function in a complementary and competitive manner in mouse embryonic stem cells to mediate proper epigenetic landscapes and gene expression. The longer isoform of DNMT3A, DNMT3A1, exhibits significant enrichment at distal promoters and canyon edges, but is excluded from proximal promoters and canyons where TET1 shows prominent binding. Deletion of Tet1 increases DNMT3A1 binding capacity at and around genes with wild-type TET1 binding. However, deletion of Dnmt3a has a minor effect on TET1 binding on chromatin, indicating that TET1 may limit DNA methylation partially by protecting its targets from DNMT3A and establishing boundaries for DNA methylation. Local CpG density may determine their complementary binding patterns and therefore that the methylation landscape is encoded in the DNA sequence. Furthermore, DNMT3A and TET1 impact histone modifications which in turn regulate gene expression. In particular, they regulate Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3 enrichment to constrain gene expression from bivalent promoters. CONCLUSIONS:We conclude that DNMT3A and TET1 regulate the epigenome and gene expression at specific targets via their functional interplay.
| S-EPMC6042404 | biostudies-literature
Project description:Natural disturbances exacerbated by novel climate regimes are increasing worldwide, threatening the ability of forest ecosystems to mitigate global warming through carbon sequestration and to provide other key ecosystem services. One way to cope with unknown disturbance events is to promote the ecological resilience of the forest by increasing both functional trait and structural diversity and by fostering functional connectivity of the landscape to ensure a rapid and efficient self-reorganization of the system. We investigated how expected and unexpected variations in climate and biotic disturbances affect ecological resilience and carbon storage in a forested region in southeastern Canada. Using a process-based forest landscape model (LANDIS-II), we simulated ecosystem responses to climate change and insect outbreaks under different forest policy scenarios-including a novel approach based on functional diversification and network analysis-and tested how the potentially most damaging insect pests interact with changes in forest composition and structure due to changing climate and management. We found that climate warming, lengthening the vegetation season, will increase forest productivity and carbon storage, but unexpected impacts of drought and insect outbreaks will drastically reduce such variables. Generalist, non-native insects feeding on hardwood are the most damaging biotic agents for our region, and their monitoring and early detection should be a priority for forest authorities. Higher forest diversity driven by climate-smart management and fostered by climate change that promotes warm-adapted species, might increase disturbance severity. However, alternative forest policy scenarios led to a higher functional and structural diversity as well as functional connectivity-and thus to higher ecological resilience-than conventional management. Our results demonstrate that adopting a landscape-scale perspective by planning interventions strategically in space and adopting a functional trait approach to diversify forests is promising for enhancing ecological resilience under unexpected global change stressors.
| S-EPMC9541346 | biostudies-literature
Project description:Proteins are flexible molecules that undergo structural changes to function. The Protein Data Bank contains multiple entries for identical proteins determined under different conditions, e.g. with and without a ligand molecule, which provides important information for understanding the structural changes related to protein functions. We gathered 839 protein structural pairs of ligand-free and ligand-bound states from monomeric or homo-dimeric proteins, and constructed the Protein Structural Change DataBase (PSCDB). In the database, we focused on whether the motions were coupled with ligand binding. As a result, the protein structural changes were classified into seven classes, i.e. coupled domain motion (59 structural changes), independent domain motion (70), coupled local motion (125), independent local motion (135), burying ligand motion (104), no significant motion (311) and other type motion (35). PSCDB provides lists of each class. On each entry page, users can view detailed information about the motion, accompanied by a morphing animation of the structural changes. PSCDB is available at http://idp1.force.cs.is.nagoya-u.ac.jp/pscdb/.
| S-EPMC3245091 | biostudies-literature
Project description:Oncogene-induced DNA methylation-mediated transcriptional silencing of tumor suppressors frequently occurs in cancer, but the mechanism and functional role of this silencing in oncogenesis are not fully understood. Here, we show that oncogenic epidermal growth factor receptor (EGFR) induces silencing of multiple unrelated tumor suppressors in lung adenocarcinomas and glioblastomas by inhibiting the DNA demethylase TET oncogene family member 1 (TET1) via the C/EBP? transcription factor. After oncogenic EGFR inhibition, TET1 binds to tumor suppressor promoters and induces their re-expression through active DNA demethylation. Ectopic expression of TET1 potently inhibits lung and glioblastoma tumor growth, and TET1 knockdown confers resistance to EGFR inhibitors in lung cancer cells. Lung cancer samples exhibited reduced TET1 expression or TET1 cytoplasmic localization in the majority of cases. Collectively, these results identify a conserved pathway of oncogenic EGFR-induced DNA methylation-mediated transcriptional silencing of tumor suppressors that may have therapeutic benefits for oncogenic EGFR-mediated lung cancers and glioblastomas.
| S-EPMC4945411 | biostudies-literature
Project description:Proteins exist as an ensemble of conformers that are distributed on free energy landscapes resembling folding funnels. While the most stable conformers populate low energy basins, protein function is often carried out through low-populated conformational states that occupy high energy basins. Ligand binding shifts the populations of these states, changing the distribution of these conformers. Understanding how the equilibrium among the states is altered upon ligand binding, interaction with other binding partners, and/or mutations and post-translational modifications is of critical importance for explaining allosteric signaling in proteins. Here, we propose a statistical analysis of the linear trajectories of NMR chemical shifts (CONCISE, COordiNated ChemIcal Shifts bEhavior) for the interpretation of protein conformational equilibria. CONCISE enables one to quantitatively measure the population shifts associated with ligand titrations and estimate the degree of collectiveness of the protein residues' response to ligand binding, giving a concise view of the structural transitions. The combination of CONCISE with thermocalorimetric and kinetic data allows one to depict a protein's approximate conformational energy landscape. We tested this method with the catalytic subunit of cAMP-dependent protein kinase A, a ubiquitous enzyme that undergoes conformational transitions upon both nucleotide and pseudo-substrate binding. When complemented with chemical shift covariance analysis (CHESCA), this new method offers both collective response and residue-specific correlations for ligand binding to proteins.
| S-EPMC4117682 | biostudies-literature