PubMed · 6686829
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1983. Genes: structure and expression.. https://pubmed.ncbi.nlm.nih.gov/6686829/
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MOTIVATION: Identifying regulatory elements in various chromosomal regions that influence gene expression is a fundamental challenge in epigenomics, with profound implications for understanding gene regulation and disease mechanisms. The advent of paired single-cell RNA sequencing and single-cell ATAC sequencing has created unprecedented opportunities to address this challenge by enabling simultaneous profiling of gene expression and chromatin accessibility at single-cell resolution. However, the inherent signals between them are weak due to the highly sparse and noisy nature of data. RESULTS: This article proposes single-cell meta-Path based Omics Embedding (scPOEM), a novel embedding method that jointly projects chromatin accessibility peaks and expressed genes into a shared low-dimensional space. By integrating the relationships among peak-peak, peak-gene, and gene-gene interactions, scPOEM assigns closer representations in the embedding space to related peak-gene pairs. Our experiments demonstrate that scPOEM generates stable representations of peaks and genes, outperforms existing methods in recovering biologically meaningful peak-gene regulatory relationships and enables new insights in subgroup and differential analysis of gene regulation. These results highlight its potential to uncover gene regulatory mechanisms and enhance the understanding of transcriptional regulation at single-cell resolution. AVAILABILITY AND IMPLEMENTATION: The source code of scPOEM is available at https://github.com/Houyt23/scPOEM. The datasets can be obtained from the 10× Genomics (https://www.10xgenomics.com/datasets/pbmc-from-a-healthy-donor-granulocytes-removed-through-cell-sorting-10-k-1-standard-1-0-0) and GEO database under access codes GSE194122 and GSE239916.
Trk receptors are a family of genes implicated in the survival, differentiation, and growth of certain neurons and tumors of the nervous system. A better understanding of the regulation of Trk receptors is relevant for developmental and oncological studies. Human neuroblastoma (NB) cell lines constitutively express low levels of TrkA mRNA, while TrkB mRNA is not readily detectable. Differentiation of NB cells is accompanied by a differential modulation of Trk expression in human NB cells. Nanomolar concentrations of RA induce a stable increase of TrkB mRNA. A transient induction of TrkA mRNA levels requires micromolar concentrations of RA. Induction of both TrkA and TrkB mRNA does not require new protein synthesis. However, RA-induced TrkB mRNA expression is transcriptionally regulated, while the transient RA-induced increase of TrkA mRNA is a consequence of extended mRNA stability. Interferon gamma (IFN-gamma) selectively increases TrkA mRNA without affecting TrkB mRNA levels. Similar to RA, IFN-gamma does not modify the transcriptional rate of TrkA mRNA, but rather increases TrkA mRNA stability. Thus, RA and IFN-gamma differentially regulate TrkA or TrkB expression in the same cell type by predominantly transcriptional (TrkB) or post transcriptional (TrkA) mechanisms. Such experiments indicate the complexity of Trk mRNA regulation and also indicate compounds that may affect neurotrophin responsiveness in developing neural cells.
BACKGROUND: Transcription by RNA polymerase II in eukaryotic cells requires the ordered assembly of general transcription factors on the promoter to form a preinitiation complex. Transcriptional activator proteins (activators) stimulate transcription by increasing the rate and/or extent of preinitiation complex assembly. We have shown previously that acidic activators increase the stable association of TFIIB on the promoter, a process we refer to as 'recruitment'. In this study, we provide evidence that diverse activators facilitate TFIIB assembly by a related mechanism. We then investigate the activator-mediated assembly of TFIIB with regard to two aspects of transcription: the distance-dependence of activator function, and reinitiation. RESULTS: We have previously described amino-acid-substitution mutants of TFIIB that are able to support an activator-independent basal level of transcription but do not respond to acidic activators. We now show that these mutants also do not respond to other classes of activators. We demonstrate that this defect is due to a failure of the activators to recruit the mutant TFIIB to the promoter. Activators often lose activity as their distance from the initiation site is increased. We show that this impaired transcriptional activity correlates with a decrease in TFIIB recruitment. Finally, we find that following the initiation of transcription, TFIIB dissociates from the promoter, requiring the activator-mediated reassembly of TFIIB in the preinitiation complex for each new round of transcription. CONCLUSION: We have provided evidence that diverse activators recruit TFIIB to the promoter by a related mechanism. This central step in transcriptional activation is sensitive to promoter architecture, and is required for each new round of transcription.