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Enhancers are located upstream or downstream of key deoxyribonucleic acid (DNA) sequences in genes and can adjust the transcription activity of neighboring genes. Identifying enhancers and determining their functions are important for understanding gene regulatory networks and expression regulatory mechanisms. However, traditional enhancer recognition relies on manual feature engineering, which is time-consuming and labor-intensive, making it difficult to perform large-scale recognition analysis. In addition, if the original dataset is too small, there is a risk of overfitting. In recent years, emerging methods, such as deep learning, have provided new insights for enhancing identification. However, these methods also present certain challenges. Deep learning models typically require a large amount of high-quality data, and data acquisition demands considerable time and resources. To address these challenges, in this paper, we propose a data-augmentation method based on generative adversarial networks to solve the problem of small datasets. Moreover, we used regularization methods such as weight decay to improve the generalizability of the model and alleviate overfitting. The Transformer encoder was used as the main component to capture the complex relationships and dependencies in enhancer sequences. The encoding layer was designed based on the principle of k-mers to preserve more information from the original DNA sequence. Compared with existing methods, the proposed approach made significant progress in enhancing the accuracy and strength of enhancer identification and prediction, demonstrating the effectiveness of the proposed method. This paper provides valuable insights for enhancer analysis and is of great significance for understanding gene regulatory mechanisms and studying disease correlations. [ABSTRACT FROM AUTHOR]

Ferroptosis is an iron-dependent form of cell death, which is reported to be associated with glioma progression and drug sensitivity. Targeting ferroptosis is a potential therapeutic approach for glioma. However, the molecular mechanism of glioma cell ferroptosis is not clear. In this study, we profile the change of 3D chromatin structure in glioblastoma ferroptosis by using HiChIP and study the 3D gene regulation network in glioblastoma ferroptosis. A combination of an analysis of HiChIP and RNA-seq data suggests that change of chromatin loops mediated by 3D chromatin structure regulates gene expressions in glioblastoma ferroptosis. Genes that are regulated by 3D chromatin structures include genes that were reported to function in ferroptosis, like HDM2 and TXNRD1. We propose a new regulatory mechanism governing glioblastoma cell ferroptosis by 3D chromatin structure. [ABSTRACT FROM AUTHOR]

The establishment and stable inheritance of individual patterns of gene expression in different cell types are required for the development of multicellular organisms. The important epigenetic regulators are the Polycomb group (PcG) and Trithorax group (TrxG) proteins, which control the silenced and active states of genes, respectively. In Drosophila, the PcG/TrxG group proteins are recruited to the DNA regulatory sequences termed the Polycomb response elements (PREs). The PREs are composed of the binding sites for different DNA-binding proteins, the so-called PcG recruiters. Currently, the role of the PcG recruiters in the targeting of the PcG proteins to PREs is well documented. However, there are examples where the PcG recruiters are also implicated in the active transcription and in the TrxG function. In addition, there is increasing evidence that the genome-wide PcG recruiters interact with the chromatin outside of the PREs and overlap with the proteins of differing regulatory classes. Recent studies of the interactomes of the PcG recruiters significantly expanded our understanding that they have numerous interactors besides the PcG proteins and that their functions extend beyond the regulation of the PRE repressive activity. Here, we summarize current data about the functions of the PcG recruiters. [ABSTRACT FROM AUTHOR]

Keratins are a family of intermediate filament-forming proteins highly specific to epithelial cells. A combination of expressed keratin genes is a defining property of the epithelium belonging to a certain type, organ/tissue, cell differentiation potential, and at normal or pathological conditions. In a variety of processes such as differentiation and maturation, as well as during acute or chronic injury and malignant transformation, keratin expression undergoes switching: an initial keratin profile changes accordingly to changed cell functions and location within a tissue as well as other parameters of cellular phenotype and physiology. Tight control of keratin expression implies the presence of complex regulatory landscapes within the keratin gene loci. Here, we highlight patterns of keratin expression in different biological conditions and summarize disparate data on mechanisms controlling keratin expression at the level of genomic regulatory elements, transcription factors (TFs), and chromatin spatial structure. [ABSTRACT FROM AUTHOR]

Nuclear receptor subfamily 5 group A member 1 (NR5A1) is expressed in the pituitary gonadotrope and regulates their differentiation. Although several regulatory regions were implicated in Nr5a1 gene expression in the pituitary gland, none of these regions have been verified using mouse models. Furthermore, the molecular functions of NR5A1 in the pituitary gonadotrope have not been fully elucidated. In the present study, we generated mice lacking the pituitary enhancer located in the 6th intron of the Nr5a1 gene. These mice showed pituitary gland-specific disappearance of NR5A1, confirming the functional importance of the enhancer. Enhancer-deleted male mice demonstrated no defects at fetal stages. Meanwhile, androgen production decreased markedly in adult, and postnatal development of reproductive organs, such as the seminal vesicle, prostate, and penis was severely impaired. We further performed transcriptomic analyses of the whole pituitary gland of the enhancer-deleted mice and controls, as well as gonadotropes isolated from Ad4BP-BAC-EGFP mice. These analyses identified several genes showing gonadotrope-specific, NR5A1-dependent expressions, such as Spp1, Tgfbr3l, Grem1, and Nr0b2. These factors are thought to function downstream of NR5A1 and play important roles in reproductive organ development through regulation of pituitary gonadotrope functions. [ABSTRACT FROM AUTHOR]

A library of active genome regulatory elements (putative promoters and enhancers) from MIA PaCa-2 pancreatic adenocarcinoma cells was constructed using a specially designed lentiviral vector and a massive parallel reporter assay (ChIP-lentiMPRA). Chromatin immunoprecipitation of the cell genomic DNA by H3K27ac antibodies was used for primary enrichment of the library for regulatory elements. Totally, 11,264 unique genome regions, many of which are capable of enhancing the expression of the CopGFP reporter gene from the minimal CMV promoter, were identified. The regions tend to be located near promoters. Based on the proximity assay, we found an enrichment of highly expressed genes among those associated with three or more mapped distal regions (2 kb distant from the 5′-ends of genes). It was shown significant enrichment of genes related to carcinogenesis or Mia PaCa-2 cell identity genes in this group. In contrast, genes associated with 1–2 distal regions or only with proximal regions (within 2 kbp of the 5′-ends of genes) are more often related to housekeeping functions. Thus, ChIP-lentiMPRA is a useful strategy for creating libraries of regulatory elements for the study of tumor-specific gene transcription. [ABSTRACT FROM AUTHOR]

The adaptive immune response in vertebrates depends on the expression of antigen-specific receptors in lymphocytes. T-cell receptor (TCR) gene expression is exquisitely regulated during thymocyte development to drive the generation of αβ and γδ T lymphocytes. The TCRα, TCRβ, TCRγ, and TCRδ genes exist in two different configurations, unrearranged and rearranged. A correctly rearranged configuration is required for expression of a functional TCR chain. TCRs can take the form of one of three possible heterodimers, pre-TCR, TCRαβ, or TCRγδ which drive thymocyte maturation into αβ or γδ T lymphocytes. To pass from an unrearranged to a rearranged configuration, global and local three dimensional (3D) chromatin changes must occur during thymocyte development to regulate gene segment accessibility for V(D)J recombination. During this process, enhancers play a critical role by modifying the chromatin conformation and triggering noncoding germline transcription that promotes the recruitment of the recombination machinery. The different signaling that thymocytes receive during their development controls enhancer activity. Here, we summarize the dynamics of long-distance interactions established through chromatin regulatory elements that drive transcription and V(D)J recombination and how different signaling pathways are orchestrated to regulate the activity of enhancers to precisely control TCR gene expression during T-cell maturation. [ABSTRACT FROM AUTHOR]

Super-enhancers (SEs) are clusters of highly active enhancers, regulating cell type-specific and disease-related genes, including oncogenes. The individual regulatory regions within SEs might be simultaneously bound by different transcription factors (TFs) and co-regulators, which together establish a chromatin environment conducting to effective transcription. While cells with distinct TF profiles can have different functions, how different cells control overlapping genetic programs remains a question. In this paper, we show that the construction of estrogen receptor alpha-driven SEs is tissue-specific, both collaborating TFs and the active SE components greatly differ between human breast cancer-derived MCF-7 and endometrial cancer-derived Ishikawa cells; nonetheless, SEs common to both cell lines have similar transcriptional outputs. These results delineate that despite the existence of a combinatorial code allowing alternative SE construction, a single master regulator might be able to determine the overall activity of SEs. [ABSTRACT FROM AUTHOR]

Broad Copy Number Gains (BCNGs) are copy-number increases of chromosomes or large segments of chromosomal arms. Publicly-available single-nucleotide polymorphism (SNP) array and RNA-Seq data of colon adenocarcinoma (COAD) samples from The Cancer Genome Atlas (TCGA) consortium allowed us to design better control groups in order to identify changes in expression due to highly recurrent BCNGs (in chromosomes 20, 8, 7, 13). We identified: (1) Overexpressed Transcripts (OverT), transcripts whose expression increases in "COAD groups bearing a specific BCNG" in comparison to "control COAD groups" not bearing it, and (2) up-regulated/down-regulated transcripts, transcripts whose expression increases/decreases in COAD groups in comparison to normal colon tissue. An analysis of gene expression reveals a correlation between the density of up-regulated genes per selected chromosome and the recurrence rate of their BCNGs. We report an enrichment of gained enhancer activity and of cancer fitness genes among OverT genes. These results support the hypothesis that the chromosomal density of overexpressed cancer fitness genes might play a significant role in the selection of gained chromosomes during cancer evolution. Analysis of functional pathways associated with OverT suggest that some multi-subunit protein complexes (eIF2, eIF3, CSTF and CPSF) are candidate targets for silencing transcriptional therapy. [ABSTRACT FROM AUTHOR]

Understanding the gene regulatory network governing cancer initiation and progression is necessary, although it remains largely unexplored. Enhancer elements represent the center of this regulatory circuit. The study aims to identify the gene expression change driven by copy number variation in enhancer elements of pancreatic adenocarcinoma (PAAD). The pancreatic tissue specific enhancer and target gene data were taken from EnhancerAtlas. The gene expression and copy number data were taken from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) and copy number variations (CNVs) were identified between matched tumor-normal samples of PAAD. Significant CNVs were matched onto enhancer coordinates by using genomic intersection functionality from BEDTools. By combining the gene expression and CNV data, we identified 169 genes whose expression shows a positive correlation with the CNV of enhancers. We further identified 16 genes which are regulated by a super enhancer and 15 genes which have high prognostic potential (Z-score > 1.96). Cox proportional hazard analysis of these genes indicates that these are better predictors of survival. Taken together, our integrative analytical approach identifies enhancer CNV-driven gene expression change in PAAD, which could lead to better understanding of PAAD pathogenesis and to the design of enhancer-based cancer treatment strategies. [ABSTRACT FROM AUTHOR]