Specific Regulatory Motifs Predict Glucocorticoid Responsiveness of Hippocampal Gene Expression

The glucocorticoid receptor (GR) is an ubiquitously expressed ligand-activated transcription factor that mediates effects of cortisol in relation to adaptation to stress. In the brain, GR affects the hippocampus to modulate memory processes through direct binding to glucocorticoid response elements (GREs) in the DNA. However, its effects are to a high degree cell specific, and its target genes in different cell types as well as the mechanisms conferring this specificity are largely unknown. To gain insight in hippocampal GR signaling, we characterized to which GRE GR binds in the rat hippocampus. Using a position-specific scoring matrix, we identified evolutionary-conserved putative GREs from a microarray based set of hippocampal target genes. Using chromatin immunoprecipitation, we were able to confirm GR binding to 15 out of a selection of 32 predicted sites (47%). The majority of these 15 GREs are previously undescribed and thus represent novel GREs that bind GR and therefore may be functional in the rat hippocampus. GRE nucleotide composition was not predictive for binding of GR to a GRE. A search for conserved flanking sequences that may predict GR-GRE interaction resulted in the identification of GC-box associated motifs, such as Myc-associated zinc finger protein 1, within 2 kb of GREs with GR binding in the hippocampus. This enrichment was not present around nonbinding GRE sequences nor around proven GR-binding sites from a mesenchymal stem-like cell dataset that we analyzed. GC-binding transcription factors therefore may be unique partners for DNA-bound GR and may in part explain cell-specific transcriptional regulation by glucocorticoids in the context of the hippocampus.

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Homeotic response elements are tightly linked to tissue-specific elements in a transcriptional enhancer of the teashirt gene

Development ◽

10.1242/dev.121.9.2799 ◽

1995 ◽

Vol 121 (9) ◽

pp. 2799-2812 ◽

Cited By ~ 4

Author(s):

A. McCormick ◽

N. Core ◽

S. Kerridge ◽

M.P. Scott

Keyword(s):

Transcriptional Activation ◽

Target Genes ◽

Hox Genes ◽

Zinc Finger Protein ◽

Cell Types ◽

Transcriptional Enhancer ◽

Hox Proteins ◽

Tissue Specific ◽

Conserved Sequences

Along the anterior-posterior axis of animal embryos, the choice of cell fates, and the organization of morphogenesis, is regulated by transcription factors encoded by clustered homeotic or ‘Hox’ genes. Hox genes function in both epidermis and internal tissues by regulating the transcription of target genes in a position- and tissue-specific manner. Hox proteins can have distinct targets in different tissues; the mechanisms underlying tissue and homeotic protein specificity are unknown. Light may be shed by studying the organization of target gene enhancers. In flies, one of the target genes is teashirt (tsh), which encodes a zinc finger protein. tsh itself is a homeotic gene that controls trunk versus head development. We identified a tsh gene enhancer that is differentially activated by Hox proteins in epidermis and mesoderm. Sites where Antennapedia (Antp) and Ultrabithorax (Ubx) proteins bind in vitro were mapped within evolutionarily conserved sequences. Although Antp and Ubx bind to identical sites in vitro, Antp activates the tsh enhancer only in epidermis while Ubx activates the tsh enhancer in both epidermis and in somatic mesoderm. We show that the DNA elements driving tissue-specific transcriptional activation by Antp and Ubx are separable. Next to the homeotic protein-binding sites are extensive conserved sequences likely to control tissue activation by different homeodomain proteins. We propose that local interactions between homeotic proteins and other factors effect activation of targets in proper cell types.

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Dpp signaling thresholds in the dorsal ectoderm of the Drosophila embryo

Development ◽

10.1242/dev.127.15.3305 ◽

2000 ◽

Vol 127 (15) ◽

pp. 3305-3312 ◽

Cited By ~ 5

Author(s):

H.L. Ashe ◽

M. Mannervik ◽

M. Levine

Keyword(s):

Gene Expression ◽

Target Genes ◽

Histone Acetyltransferase ◽

Cell Types ◽

Drosophila Embryo ◽

Present Evidence ◽

Drosophila Homolog ◽

Dorsal Ectoderm ◽

Transgenic Embryos ◽

Different Cell Types

The dorsal ectoderm of the Drosophila embryo is subdivided into different cell types by an activity gradient of two TGF(β) signaling molecules, Decapentaplegic (Dpp) and Screw (Scw). Patterning responses to this gradient depend on a secreted inhibitor, Short gastrulation (Sog) and a newly identified transcriptional repressor, Brinker (Brk), which are expressed in neurogenic regions that abut the dorsal ectoderm. Here we examine the expression of a number of Dpp target genes in transgenic embryos that contain ectopic stripes of Dpp, Sog and Brk expression. These studies suggest that the Dpp/Scw activity gradient directly specifies at least three distinct thresholds of gene expression in the dorsal ectoderm of gastrulating embryos. Brk was found to repress two target genes, tailup and pannier, that exhibit different limits of expression within the dorsal ectoderm. These results suggest that the Sog inhibitor and Brk repressor work in concert to establish sharp dorsolateral limits of gene expression. We also present evidence that the activation of Dpp/Scw target genes depends on the Drosophila homolog of the CBP histone acetyltransferase.

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Single-cell RNA-Seq Reveals Transcriptional Landscape and Intra-tumor Heterogenicity in Gallbladder Cancer Liver Metastasis Microenvironment

10.21203/rs.3.rs-117830/v1 ◽

2020 ◽

Author(s):

Wenhua You ◽

Xiangyu Li ◽

Peng Wang ◽

Bowen Sha ◽

Yuan Liang ◽

...

Keyword(s):

T Cells ◽

Liver Metastasis ◽

Gallbladder Cancer ◽

Single Cell ◽

Molecular Mechanisms ◽

Cell Types ◽

Malignant Cells ◽

Different Cell Types ◽

High Degree

Abstract Background: Gallbladder cancer (GBC) is a highly aggressive biliary epithelial malignancy. Tumor invasion and metastasis contributed to the high mortality of GBC patients. However, molecular mechanisms involved in GBC metastases are still little known. Methods: We performed single-cell RNA sequencing on GBC liver metastasis tissue and analyzed the data based on different cell types.Results: In this study, 8 cell types, including T cells, B cells, malignant cells, fibroblasts, endothelial cells, macrophages, dendritic cells, and mast cells were identified. Malignant cells displayed a high degree of intra-tumor heterogenicity and neutrophils could promote GBC progression in vitro. Besides, cytotoxic CD8+ T cells became exhausted and CD4+ Tregs presented immunosuppressive characteristics. Macrophages played an important role in the tumor microenvironment. We identified three distinct macrophage subsets and emerged M2 polarization. We also found that cancer-associated fibroblasts exhibited heterogeneity and promoted GBC metastasis. Conclusions: In conclusion, our work provided a landscape view at the single-cell level and may clear the way for the therapy of GBC metastases.

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Capturing large genomic contexts for accurately predicting enhancer-promoter interactions

10.1101/2021.09.04.458817 ◽

2021 ◽

Author(s):

Ken Chen ◽

Huiying Zhao ◽

Yuedong Yang

Keyword(s):

Target Gene ◽

Target Genes ◽

Cell Types ◽

Training Data ◽

Independent Test ◽

Distant Target ◽

Comparable Performance ◽

Precision Recall Curve ◽

Different Cell Types ◽

The Impact

AbstractAccurately identifying enhancer-promoter interactions (EPIs) is challenging because enhancers usually act on the promoters of distant target genes. Although a variety of machine learning and deep learning models have been developed, many of them are not designed to or could not be well applied to predict EPIs in cell types different from the training data. In this study, we develop the TransEPI model for EPI prediction based on datasets derived from Hi-C and ChIA-PET data. TransEPI compiles genomic features from large intervals harboring the enhancer-promoter pair and adopts a Transformer-based architecture to capture the long-range dependencies. Thus, TransEPI could achieve more accurate prediction by addressing the impact of other genomic loci that may competitively interact with the enhancer-promoter pair. We evaluate TransEPI in a challenging scenario, where the independent test samples are predicted by models trained on the data from different cell types and chromosomes. TransEPI robustly predicts cross-cell-type EPI prediction by achieving comparable performance in cross-validation and independent test. More importantly, TransEPI significantly outperforms the state-of-the-art EPI models on the independent test datasets, with the Area Under Precision-Recall Curve (auPRC) score increasing by 48.84 % on average. Hence, TransEPI is applicable for accurate EPI prediction in cell types without chromatin structure data. Moreover, we find the TransEPI framework could also be extended to identify the target gene of non-coding mutations, which may facilitate studying pathogenic non-coding mutations.

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A conserved expression signature predicts growth rate and reveals cell & lineage-specific differences

10.1101/782037 ◽

2019 ◽

Author(s):

Zhisheng Jiang ◽

Serena Francesca Generoso ◽

Marta Badia ◽

Bernhard Payer ◽

Lucas B. Carey

Keyword(s):

Cell Lineage ◽

Gene Expression Signature ◽

Cell Types ◽

Eukaryotic Cell ◽

Rna Seq ◽

Cell Type Specificity ◽

Expression Signature ◽

Differentiated Cells ◽

Different Cell Types ◽

High Degree

By performing RNA-seq on cells FACS sorted by their proliferation rate, this study identifies a gene expression signature capable of predicting proliferation rates in diverse eukaryotic cell types and species. This signature, applied to scRNAseq data from C.elegans, reveals lineage-specific differences in proliferation during development. In contrast to the universality of the proliferation signature, mitochondria and metabolism related genes show a high degree of cell-type specificity; mouse pluripotent stem cells (mESCs) and differentiated cells (fibroblasts) exhibit opposite relations between mitochondria state and proliferation. Furthermore, we identified a slow proliferating subpopulation of mESCs with higher expression of pluripotency genes. Finally, we show that fast and slow proliferating subpopulations are differentially sensitive to mitochondria inhibitory drugs in different cell types.

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Epigenetic Regulation Mediated by miRNA in the Susceptibility and Pathogenesis of Rheumatoid Arthritis

10.20944/preprints202004.0241.v1 ◽

2020 ◽

Author(s):

Shicheng Guo ◽

Cen Chang ◽

Lingxia Xu ◽

Runrun Zhang ◽

Yehua Jin ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Therapeutic Intervention ◽

Target Genes ◽

Cell Types ◽

Micro Rna ◽

Current Evidence ◽

Diagnosis And Prognosis ◽

Transcriptome Regulation ◽

Therapy Target ◽

Different Cell Types

micro-RNA (miRNA) has been demonstrated to play important roles in the transcriptome regulation and disease development including cancer and autoimmune disease such as rheumatoid arthritis. However, a comprehensive map on how the mRNAs regulate transcripts, pathways, immune system differentiation and interaction with terminal cells like T-cells, fibroblast-like synoviocytes (FLS), osteoblast and osteoclast still unknown. In this review, we have provided a thorough summary on the roles of miRNAs in the susceptibility, pathogenesis, diagnosis, therapeutic intervention and prognosis. Numerous miRNAs were found abnormally expressed in rheumatoid arthritis relevant cells and regulated the target genes and pathways like NF-κB, Fas-FasL, JAK-STAT, IRE1-RIDD, mTOR pathway. In addition, miRNA act as gene expression regulators affect the T-cell differentiate to different cell types including Th17 and T-reg cells which provide promising gene therapy target to regulate immune systems in rheumatoid arthritis. We also summarized interesting diagnosis and prognosis roles of blood and cell-free based miRNAs which provided novel opportunity to work together with rheumatoid factors (RF), anti-CCP to provide accurate diagnosis and prognosis especially for seronegative patients. Furthermore, functional genetic variants in miRNA-499 and miRNA-146a explained part of missing susceptibility of rheumatoid arthritis. Finally, miRNAs were showed as promising biomarker to indicate the DMRDS and immunotherapy efficiency, drug response and resistance. What’s more, autotherapeutic effect of miRNA intervention provided promising to develop miRNA based rheumatoid arthritis drugs. Overall, current evidence supports miRNAs as the interesting targets to better understand the pathogenetic mechanism and therapeutic intervention of rheumatoid arthritis.

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The Role of MicroRNAs in Regulatory T Cells

Journal of Immunology Research ◽

10.1155/2020/3232061 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Chao Liu ◽

Nannan Li ◽

Guijian Liu

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Immune Responses ◽

Small Rnas ◽

Target Genes ◽

Cell Types ◽

Immune Disorders ◽

Ongoing Research ◽

Different Cell Types

MicroRNAs are a class of conserved, 20 nt-23 nt long, noncoding small RNAs that inhibit expression of their respective target genes in different cell types. Regulatory T cells (Tregs) are a subpopulation of T cells that negatively regulate immune responses, which is essential to immune homeostasis. Recent studies have indicated that microRNAs play an important role in the proliferation, differentiation, and functions of Treg. Here, we review the recent progress in understanding the roles of microRNAs in Treg and their dysregulation in immune-related diseases. This ongoing research continues to expand the understanding of Treg regulation and the mechanisms of immune disorders.

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Genetic Analysis of Adenohypophysis Formation in Zebrafish

Molecular Endocrinology ◽

10.1210/me.2003-0376 ◽

2004 ◽

Vol 18 (5) ◽

pp. 1185-1195 ◽

Cited By ~ 38

Author(s):

Wiebke Herzog ◽

Carmen Sonntag ◽

Brigitte Walderich ◽

Jörg Odenthal ◽

Hans-Martin Maischein ◽

...

Keyword(s):

Positional Cloning ◽

Cell Types ◽

Pituitary Cells ◽

Vertebrate Species ◽

Spontaneous Mutations ◽

Pituitary Development ◽

The Third ◽

Adenohypophyseal Cell ◽

Different Cell Types ◽

High Degree

Abstract The adenohypophysis consists of at least six different cell types, somatotropes, lactotropes, thyrotropes, melanotropes, corticotropes, and gonadotropes. In mouse, cloning of spontaneous mutations and gene targeting has revealed multiple genes required for different steps of adenohypophysis development. Here, we report the results of a systematic search for genes required for adenohypophysis formation and patterning in zebrafish. By screening F3 offspring of N-ethyl-N-nitrosourea-mutagenized founder fish, we isolated eleven mutants with absent or reduced expression of GH, the product of somatotropes, but a normally developing hypothalamus. Of such mutants, eight were further analyzed and mapped. They define four genes essential for different steps of adenohypophysis development. Two of them, lia and pia, affect the entire adenohypophysis, whereas the other two are required for a subset of adenohypophyseal cell types only. The third gene is zebrafish pit1 and is required for lactotropes, thyrotropes, and somatotropes, similar to its mouse ortholog, whereas the fourth, aal, is required for corticotropes, melanotropes, thyrotropes, and somatotropes, but not lactotropes. In conclusion, the isolated zebrafish mutants confirm principles of adenohypophysis development revealed in mouse, thereby demonstrating the high degree of molecular and mechanistic conservation among the different vertebrate species. In addition, they point to thus far unknown features of adenohypophysis development, such as the existence of a new lineage of pituitary cells, which partially overlaps with the Pit1 lineage. Positional cloning of the lia, pia, and aal genes might reveal novel regulators of vertebrate pituitary development.

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The Structure and Function Of Intermediate Filament Networks In Mammalian Cells

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100120382 ◽

1985 ◽

Vol 43 ◽

pp. 752-755

Author(s):

Robert D. Goldman ◽

Anne Goldman ◽

Jonathan Jones ◽

Linda Parysek

Keyword(s):

Nerve Cell ◽

Mammalian Cells ◽

Protein Composition ◽

Cell Types ◽

Structural Subunit ◽

Filament Networks ◽

Cell Shape Formation ◽

And Function ◽

Different Cell Types ◽

High Degree

Intermediate filaments (IF) are major cytoskeletal components found in most mammalian cells. One of the most intriguing properties of IF is their high degree of variability with regard to their structural subunit proteins. This ariability is most evident when one compares the protein composition of IF from different cell types. For example, nerve cell IF (neurofilaments) contain the so-called neurofilament triplet proteins, while different epithelial cells contain two or more of the family of IF proteins called keratins. Indeed other cell types appear to have primarily a single subunit species such as in fibroblasts (vimentin, decamin) and muscle cells (desmin).In the specific case of the nervous system, there is very little information available on specific functions of neurofilaments, although they are thought to be involved in nerve cell shape formation and maintenance, as well as in axoplasmic transport and flow.

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