Similar Datasets
Project description:Transcription factor (TF)-cofactor (COF) interactions define dynamic, cell-specific networks that govern gene expression; however, these networks are understudied due to a lack of methods for high-throughput profiling of DNA-bound TF-COF complexes. Here we describe the Cofactor Recruitment (CoRec) method for rapid profiling of cell-specific TF-COF complexes. We define a lysine acetyltransferase (KAT)-TF network in resting and stimulated T cells. We find promiscuous recruitment of KATs for many TFs and that 35% of KAT-TF interactions are condition specific. KAT-TF interactions identify NF-κB as a primary regulator of acutely induced H3K27ac. Finally, we find that heterotypic clustering of CBP/P300-recruiting TFs is a strong predictor of total promoter H3K27ac. Our data supports clustering of TF sites that broadly recruit KATs as a mechanism for widespread co-occurring histone acetylation marks. CoRec can be readily applied to different cell systems and provides a powerful approach to define TF-COF networks impacting chromatin state and gene regulation.
2024-06-30 | GSE266126 | GEO
Project description:Transcription factor (TF)-cofactor (COF) interactions define dynamic, cell-specific networks that govern gene expression; however, these networks are understudied due to a lack of methods for high-throughput profiling of DNA-bound TF-COF complexes. Here we describe the Cofactor Recruitment (CoRec) method for rapid profiling of cell-specific TF-COF complexes. We define a lysine acetyltransferase (KAT)-TF network in resting and stimulated T cells. We find promiscuous recruitment of KATs for many TFs and that 35% of KAT-TF interactions are condition specific. KAT-TF interactions identify NF-κB as a primary regulator of acutely induced H3K27ac. Finally, we find that heterotypic clustering of CBP/P300-recruiting TFs is a strong predictor of total promoter H3K27ac. Our data supports clustering of TF sites that broadly recruit KATs as a mechanism for widespread co-occurring histone acetylation marks. CoRec can be readily applied to different cell systems and provides a powerful approach to define TF-COF networks impacting chromatin state and gene regulation.
2024-06-30 | GSE266125 | GEO
Project description:Dynamic cellular processes such as differentiation are driven by changes in the abundances of transcription factors (TFs). However, despite years of studies, our knowledge about the protein copy number of TFs in the nucleus is limited. Here, by determining the absolute abundances of 103 TFs and co-factors during the course of human erythropoiesis, we provide a dynamic and quantitative scale for TFs in the nucleus. Furthermore, we establish the first gene regulatory network of cell fate commitment that integrates temporal protein stoichiometry data with mRNA measurements. The model revealed quantitative imbalances in TFs' cross-antagonistic relationships that underlie lineage determination. Finally, we made the surprising discovery that, in the nucleus, co-repressors are dramatically more abundant than co-activators at the protein level, but not at the RNA level, with profound implications for understanding transcriptional regulation. These analyses provide a unique quantitative framework to understand transcriptional regulation of cell differentiation in a dynamic context.
| S-EPMC7344268 | biostudies-literature
Project description:BackgroundThe study of biological interaction networks is a central theme of systems biology. Here, we investigate the relationships between two distinct types of interaction networks: the metabolic pathway map and the protein-protein interaction network (PIN). It has long been established that successive enzymatic steps are often catalyzed by physically interacting proteins forming permanent or transient multi-enzymes complexes. Inspecting high-throughput PIN data, it was shown recently that, indeed, enzymes involved in successive reactions are generally more likely to interact than other protein pairs. In our study, we expanded this line of research to include comparisons of the underlying respective network topologies as well as to investigate whether the spatial organization of enzyme interactions correlates with metabolic efficiency.ResultsAnalyzing yeast data, we detected long-range correlations between shortest paths between proteins in both network types suggesting a mutual correspondence of both network architectures. We discovered that the organizing principles of physical interactions between metabolic enzymes differ from the general PIN of all proteins. While physical interactions between proteins are generally dissortative, enzyme interactions were observed to be assortative. Thus, enzymes frequently interact with other enzymes of similar rather than different degree. Enzymes carrying high flux loads are more likely to physically interact than enzymes with lower metabolic throughput. In particular, enzymes associated with catabolic pathways as well as enzymes involved in the biosynthesis of complex molecules were found to exhibit high degrees of physical clustering. Single proteins were identified that connect major components of the cellular metabolism and may thus be essential for the structural integrity of several biosynthetic systems.ConclusionOur results reveal topological equivalences between the protein interaction network and the metabolic pathway network. Evolved protein interactions may contribute significantly towards increasing the efficiency of metabolic processes by permitting higher metabolic fluxes. Thus, our results shed further light on the unifying principles shaping the evolution of both the functional (metabolic) as well as the physical interaction network.
| S-EPMC2607255 | biostudies-literature
Project description:Network biology aims to understand cell behavior through the analysis of underlying complex biomolecular networks. Inference of condition-specific interaction networks from epigenomic data enables the characterization of the structural plasticity that regulatory networks can acquire in different tissues of the same organism. From this perspective, uncovering specific patterns of variation by comparing network structure among tissues could provide insights into systems-level mechanisms underlying cell behavior. Following this idea, here we propose an empirical framework to analyze mammalian tissue-specific networks, focusing on characterizing and contrasting their structure and behavior in response to perturbations. We structurally represent the state of the cell/tissue by condition specific transcription factor networks generated using DNase-seq chromatin accessibility data, and we profile their systems behavior in terms of the structural robustness against random and directed perturbations. Using this framework, we unveil the structural heterogeneity existing among tissues at different levels of differentiation. We uncover a novel and conserved systems property of regulatory networks underlying embryonic stem cells (ESCs): in contrast to terminally differentiated tissues, the promiscuous regulatory connectivity of ESCs produces a globally homogeneous network resulting in increased structural robustness. We show that this property is associated with a more permissive, less restrictive chromatin accesibility state in ESCs. Possible biological consequences of this property are discussed.
| S-EPMC6141546 | biostudies-literature
Project description:The oncoprotein transcription factor MYC is overexpressed in the majority of cancers. Key to its oncogenic activity is the ability of MYC to regulate gene expression patterns that drive and maintain the malignant state. MYC is also considered a validated anticancer target, but efforts to pharmacologically inhibit MYC have failed. The dependence of MYC on cofactors creates opportunities for therapeutic intervention, but for any cofactor this requires structural understanding of how the cofactor interacts with MYC, knowledge of the role it plays in MYC function, and demonstration that disrupting the cofactor interaction will cause existing cancers to regress. One cofactor for which structural information is available is WDR5, which interacts with MYC to facilitate its recruitment to chromatin. To explore whether disruption of the MYC-WDR5 interaction could potentially become a viable anticancer strategy, we developed a Burkitt's lymphoma system that allows replacement of wild-type MYC for mutants that are defective for WDR5 binding or all known nuclear MYC functions. Using this system, we show that WDR5 recruits MYC to chromatin to control the expression of genes linked to biomass accumulation. We further show that disrupting the MYC-WDR5 interaction within the context of an existing cancer promotes rapid and comprehensive tumor regression in vivo. These observations connect WDR5 to a core tumorigenic function of MYC and establish that, if a therapeutic window can be established, MYC-WDR5 inhibitors could be developed as anticancer agents.
| S-EPMC6911241 | biostudies-literature
Project description:Exposure to stress is associated with adverse emotional and behavioral responses. Whereas the ?-opioid receptor (KOR) system is known to mediate some of the effects, it is unclear whether and how stress affects epigenetic regulation of this gene. Because the KOR gene can use two promoters (Pr1 and Pr2) and two polyadenylation signals (PA1 and PA2), it is also interesting whether and how these distinct regulatory mechanisms are differentially modulated by stress. The current study examined the effects of stress on these different regulatory mechanisms of the KOR gene. Results showed that stress selectively increased the expression of KOR mRNA isoforms controlled by Pr1 and terminated at PA1 in specific brain areas including the medial-prefrontal cortex, hippocampus, brainstem, and sensorimotor cortex, but not in the amygdala or hypothalamus. These effects correlated with altered epigenetic state of KOR Pr1 chromatin, as well as elevation and increased recruitment of the principal transcription factor c-Myc, which could activate Pr1. Stress-induced modulation of Pr1 was further validated using glutamate-sensitive murine hippocampal cell line, HT22. The results revealed a common molecular mechanism underlying the effect of stress on selected chromatin regions of this gene at the cellular level and in the context of whole animal and identified a critical role for c-Myc in stress-triggered epigenetic regulation of the KOR gene locus. This study sheds light on the mechanisms of stress-induced epigenetic regulation that targets specific chromatin segments and suggests certain KOR transcripts and its principal transcription factor c-Myc as potential targets for brain-area-specific intervention.
| S-EPMC3384167 | biostudies-literature
Project description:Organisms determine the transcription rates of thousands of genes through a few modes of regulation that recur across the genome1. These modes interact with a changing cellular environment to yield highly dynamic expression patterns2. In bacteria, the relationship between a gene's regulatory architecture and its expression is well understood for individual model gene circuits3,4. However, a broader perspective of these dynamics at the genome-scale is lacking, in part because bacterial transcriptomics have hitherto captured only a static snapshot of expression averaged across millions of cells5. As a result, the full diversity of gene expression dynamics and their relation to regulatory architecture remains unknown. Here we present a novel genome-wide classification of regulatory modes based on each gene's transcriptional response to its own replication, which we term the Transcription-Replication Interaction Profile (TRIP). We found that the response to the universal perturbation of chromosomal replication integrates biological regulatory factors with biophysical molecular events on the chromosome to reveal a gene's local regulatory context. While the TRIPs of many genes conform to a gene dosage-dependent pattern, others diverge in distinct ways, including altered timing or amplitude of expression, and this is shaped by factors such as intra-operon position, repression state, or presence on mobile genetic elements. Our transcriptome analysis also simultaneously captures global properties, such as the rates of replication and transcription, as well as the nestedness of replication patterns. This work challenges previous notions of the drivers of expression heterogeneity within a population of cells, and unearths a previously unseen world of gene transcription dynamics.
| S-EPMC10081379 | biostudies-literature
Project description:We present TADsplimer, the first computational tool to systematically detect topologically associating domain (TAD) splits and mergers across the genome between Hi-C samples. TADsplimer recaptures splits and mergers of TADs with high accuracy in simulation analyses and defines hundreds of TAD splits and mergers between pairs of different cell types, such as endothelial cells and fibroblasts. Our work reveals a key role for TAD remodeling in epigenetic regulation of transcription and delivers the first tool for the community to perform dynamic analysis of TAD splits and mergers in numerous biological and disease models.
| S-EPMC7114812 | biostudies-literature
Project description:All organisms regulate transcription of their genes. To understand this process, a complete understanding of how transcription factors find their targets in cellular nuclei is essential. The DNA sequence and other variables are known to influence this binding, but the distribution of transcription factor binding patterns remains mostly unexplained in metazoan genomes. Here, we investigate the role of chromosome conformation in the trajectories of transcription factors. Using molecular dynamics simulations, we uncover the principles of their diffusion on chromatin. Chromosome contacts play a conflicting role: at low density they enhance transcription factor traffic, but at high density they lower it by volume exclusion. Consistently, we observe that in human cells, highly occupied targets, where protein binding is promiscuous, are found at sites engaged in chromosome loops within uncompacted chromatin. In summary, we provide a framework for understanding the search trajectories of transcription factors, highlighting the key contribution of genome conformation.
| S-EPMC5928121 | biostudies-literature