Duplication of a promiscuous transcription factor drives the emergence of a new regulatory network.
Ontology highlight
ABSTRACT:
SUBMITTER: Pougach K
PROVIDER: S-EPMC4172970 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Human embryonic stem cells (ESCs) offer a promising therapeutic approach for osteoarthritis (OA). The unlimited source of cells capable of differentiating to chondrocytes has potential for repairing damaged cartilage or to generate disease models via gene editing. However their use is limited by the efficiency of chondrogenic differentiation. An improved understanding of the transcriptional and post-transcriptional regulation of chondrogenesis will enable us to improve hESC chondrogenic differentiation protocols. Small RNA-seq and whole transcriptome sequencing was performed on distinct stages of hESC-directed chondrogenesis. This revealed significant changes in the expression of several microRNAs including upregulation of known cartilage associated microRNAs and those transcribed from the Hox complexes, and the downregulation of pluripotency associated microRNAs. Integration of miRomes and transcriptomes generated during hESC-directed chondrogenesis identified key functionally related clusters of co-expressed microRNAs and protein coding genes, associated with pluripotency, primitive streak, limb development and extracellular matrix. Analysis identified regulators of hESC-directed chondrogenesis such as miR-29c-3p with 10 of its established targets identified as co-regulated 'ECM organisation' genes and miR-22-3p which is highly co-expressed with ECM genes and may regulate these genes indirectly by targeting the chondrogenic regulators SP1 and HDAC4. We identified several upregulated transcription factors including HOXA9/A10/D13 involved in limb patterning and RELA, JUN and NFAT5, which have targets enriched with ECM associated genes. We have developed an unbiased approach for integrating transcriptome and miRome using protein-protein interactions, transcription factor regulation and miRNA target interactions and identified key regulatory networks prominent in hESC chondrogenesis.
| S-EPMC7075910 | biostudies-literature
Project description:Cell identity is specified by a core transcriptional regulatory circuitry (CoRC), typically limited to a small set of interconnected cell-specific transcription factors (TFs). By mining global hepatic TF regulons, we reveal a more complex organization of the transcriptional regulatory network controlling hepatocyte identity. We show that tight functional interconnections controlling hepatocyte identity extend to non-cell-specific TFs beyond the CoRC, which we call hepatocyte identity (Hep-ID)CONNECT TFs. Besides controlling identity effector genes, Hep-IDCONNECT TFs also engage in reciprocal transcriptional regulation with TFs of the CoRC. In homeostatic basal conditions, this translates into Hep-IDCONNECT TFs being involved in fine tuning CoRC TF expression including their rhythmic expression patterns. Moreover, a role for Hep-IDCONNECT TFs in the control of hepatocyte identity is revealed in dedifferentiated hepatocytes where Hep-IDCONNECT TFs are able to reset CoRC TF expression. This is observed upon activation of NR1H3 or THRB in hepatocarcinoma or in hepatocytes subjected to inflammation-induced loss of identity. Our study establishes that hepatocyte identity is controlled by an extended array of TFs beyond the CoRC.
| S-EPMC10481658 | biostudies-literature
Project description:BackgroundMicroRNA (miRNA) is a class of small RNAs of ~22nt which play essential roles in many crucial biological processes and numerous human diseases at post-transcriptional level of gene expression. It has been revealed that miRNA genes tend to be clustered, and the miRNAs organized into one cluster are usually transcribed coordinately. This implies a coordinated regulation mode exerted by clustered miRNAs. However, how the clustered miRNAs coordinate their regulations on large scale gene expression is still unclear.ResultsWe constructed the miRNA-transcription factor regulatory network that contains the interactions between transcription factors (TFs), miRNAs and non-TF protein-coding genes, and made a genome-wide study on the regulatory coordination of clustered miRNAs. We found that there are two types of miRNA clusters, i.e. homo-clusters that contain miRNAs of the same family and hetero-clusters that contain miRNAs of various families. In general, the homo-clustered as well as the hetero-clustered miRNAs both exhibit coordinated regulation since the miRNAs belonging to one cluster tend to be involved in the same network module, which performs a relatively isolated biological function. However, the homo-clustered miRNAs show a direct regulatory coordination that is realized by one-step regulation (i.e. the direct regulation of the coordinated targets), whereas the hetero-clustered miRNAs show an indirect regulatory coordination that is realized by a regulation comprising at least three steps (e.g. the regulation on the coordinated targets by a miRNA through a sequential action of two TFs). The direct and indirect regulation target different categories of genes, the former predominantly regulating genes involved in emergent responses, the latter targeting genes that imply long-term effects.ConclusionThe genomic clustering of miRNAs is closely related to the coordinated regulation in the gene regulatory network. The pattern of regulatory coordination is dependent on the composition of the miRNA cluster. The homo-clustered miRNAs mainly coordinate their regulation rapidly, while the hetero-clustered miRNAs exert control with a delay. The diverse pattern of regulatory coordination suggests distinct roles of the homo-clustered and the hetero-clustered miRNAs in biological processes.
| S-EPMC3262773 | biostudies-literature
Project description:Cell identity is specified by a core transcriptional regulatory circuitry (CoRC), typically limited to a small set of interconnected cell-specific transcription factors (TFs). By mining global hepatic TF regulons, we reveal a more complex organization of the transcriptional regulatory network controlling hepatocyte identity. We show that tight functional interconnections controlling hepatocyte identity extend to non-cell-specific TFs beyond the CoRC, which we call hepatocyte identity (Hep-ID)CONNECT TFs. Besides controlling identity effector genes, Hep-IDCONNECT TFs also engage in reciprocal transcriptional regulation with TFs of the CoRC. In homeostatic basal conditions, this translates into Hep-IDCONNECT TFs being involved in fine tuning CoRC TF expression including their rhythmic expression patterns. Moreover, a role for Hep-IDCONNECT TFs in the control of hepatocyte identity is revealed in dedifferentiated hepatocytes where Hep-IDCONNECT TFs are able to reset CoRC TF expression. This is observed upon activation of NR1H3 or THRB in hepatocarcinoma or in hepatocytes subjected to inflammation-induced loss of identity. Our study establishes that hepatocyte identity is controlled by an extended array of TFs beyond the CoRC.
| S-SCDT-10_15252-EMBR_202357020 | biostudies-other
Project description:BackgroundInflammation triggered by infection or injury is tightly controlled by glucocorticoid hormones which signal via a dedicated transcription factor, the Glucocorticoid Receptor (GR), to regulate hundreds of genes. However, the hierarchy of transcriptional responses to GR activation and the molecular basis of their oftentimes non-linear dynamics are not understood.ResultsWe investigated early glucocorticoid-driven transcriptional events in macrophages, a cell type highly responsive to both pro- and anti-inflammatory stimuli. Using whole transcriptome analyses in resting and acutely lipopolysaccharide (LPS)-stimulated macrophages, we show that early GR target genes form dense networks with the majority of control nodes represented by transcription factors. The expression dynamics of several glucocorticoid-responsive genes are consistent with feed forward loops (FFL) and coincide with rapid GR recruitment. Notably, GR binding sites in genes encoding members of the KLF transcription factor family colocalize with KLF binding sites. Moreover, our gene expression, transcription factor binding and computational data are consistent with the existence of the GR-KLF9-KLF2 incoherent FFL. Analysis of LPS-downregulated genes revealed striking enrichment in multimerized Zn-fingers- and KRAB domain-containing proteins known to bind nucleic acids and repress transcription by propagating heterochromatin. This raises an intriguing possibility that an increase in chromatin accessibility in inflammatory macrophages results from broad downregulation of negative chromatin remodelers.ConclusionsPro- and anti-inflammatory stimuli alter the expression of a vast array of transcription factors and chromatin remodelers. By regulating multiple transcription factors, which propagate the initial hormonal signal, GR acts as a coordinating hub in anti-inflammatory responses. As several KLFs promote the anti-inflammatory program in macrophages, we propose that GR and KLFs functionally cooperate to curb inflammation.
| S-EPMC4133603 | biostudies-literature
Project description:Transcription factors (TFs) are key nodes of regulatory networks in eukaryotic organisms, including filamentous fungi such as Neurospora crassa. The 178 predicted DNA-binding TFs in N. crassa are distributed primarily among six gene families, which represent an ancient expansion in filamentous ascomycete genomes; 98 TF genes show detectable expression levels during vegetative growth of N. crassa, including 35 that show a significant difference in expression level between hyphae at the periphery versus hyphae in the interior of a colony. Regulatory networks within a species genome include paralogous TFs and their respective target genes (TF regulon). To investigate TF network evolution in N. crassa, we focused on the basic leucine zipper (bZIP) TF family, which contains nine members. We performed baseline transcriptional profiling during vegetative growth of the wild-type and seven isogenic, viable bZIP deletion mutants. We further characterized the regulatory network of one member of the bZIP family, NCU03905. NCU03905 encodes an Ap1-like protein (NcAp-1), which is involved in resistance to multiple stress responses, including oxidative and heavy metal stress. Relocalization of NcAp-1 from the cytoplasm to the nucleus was associated with exposure to stress. A comparison of the NcAp-1 regulon with Ap1-like regulons in Saccharomyces cerevisiae, Schizosaccharomyces pombe, Candida albicans and Aspergillus fumigatus showed both conservation and divergence. These data indicate how N. crassa responds to stress and provide information on pathway evolution.
| S-EPMC3081083 | biostudies-literature
Project description:The noncoding genome is pervasively transcribed. Noncoding RNAs (ncRNAs) generated from enhancers have been proposed as a general facet of enhancer function and some have been shown to be required for enhancer activity. Here we examine the transcription-factor-(TF)-dependence of ncRNA expression to define enhancers and enhancer-associated ncRNAs that are involved in a TF-dependent regulatory network. TBX5, a cardiac TF, regulates a network of cardiac channel genes to maintain cardiac rhythm. We deep sequenced wildtype and Tbx5-mutant mouse atria, identifying ~2600 novel Tbx5-dependent ncRNAs. Tbx5-dependent ncRNAs were enriched for tissue-specific marks of active enhancers genome-wide. Tbx5-dependent ncRNAs emanated from regions that are enriched for TBX5-binding and that demonstrated Tbx5-dependent enhancer activity. Tbx5-dependent ncRNA transcription provided a quantitative metric of Tbx5-dependent enhancer activity, correlating with target gene expression. We identified RACER, a novel Tbx5-dependent long noncoding RNA (lncRNA) required for the expression of the calcium-handling gene Ryr2. We illustrate that TF-dependent enhancer transcription can illuminate components of TF-dependent gene regulatory networks.
| S-EPMC5745077 | biostudies-literature
Project description:BackgroundTranscription factors (TFs) play a key role in regulating plant development and response to environmental stimuli. While most genes revert to single copy after whole genome duplication (WGD) event, transcription factors are retained at a significantly higher rate. Little is known about how TF duplicates have diverged in their expression and regulation, the answer to which may contribute to a better understanding of the elevated retention rate among TFs.ResultsHere we assessed what features may explain differences in the retention of TF duplicates and other genes using Arabidopsis thaliana as a model. We integrated 34 expression, sequence, and conservation features to build a linear model for predicting the extent of duplicate retention following WGD events among TFs and 19 groups of genes with other functions. We found that TFs was the least well predicted, demonstrating the features of TFs are substantially deviated from duplicate genes in other function groups. Consistent with this, the evolution of TF expression patterns and cis-regulatory cites favors the partitioning of ancestral states among the resulting duplicates: one "ancestral" TF duplicate retains most ancestral expression and cis-regulatory sites, while the "non-ancestral" duplicate is enriched for novel regulatory sites. By modeling the retention of ancestral expression and cis-regulatory states in duplicate pairs using a system of differential equations, we found that TF duplicate pairs in a partitioned state are preferentially maintained.ConclusionsThese TF duplicates with asymmetrically partitioned ancestral states are likely maintained because one copy retains ancestral functions while the other, at least in some cases, acquires novel cis-regulatory sites that may be important for novel, adaptive traits.
| S-EPMC6416927 | biostudies-literature
Project description:The completion of the zebrafish genome sequence and advances in miniaturization and multiplexing were essential to the creation of techniques such as RNA-seq, ChIP-seq, and high-throughput behavioral and chemical screens. Multiplexing was also instrumental in the recent enhancement of the classic yeast one-hybrid interaction techniques to provide unprecedented discovery capabilities for protein-DNA interactions. Unfortunately its use for zebrafish research is currently hampered by the lack of an open reading frame (ORF) clone collection. As a first step toward a complete collection, we describe a small library of transcriptional regulatory proteins comprising 142 ORFs and its potential applications.
| S-EPMC6112160 | biostudies-literature
Project description:Schizophrenia is a complex brain disorder with molecular mechanisms that have yet to be elucidated. Previous studies have suggested that changes in gene expression may play an important role in the etiology of schizophrenia, and that microRNAs (miRNAs) and transcription factors (TFs) are primary regulators of this gene expression. So far, several miRNA-TF mediated regulatory modules have been verified. We hypothesized that miRNAs and TFs might play combinatory regulatory roles for schizophrenia genes and, thus, explored miRNA-TF regulatory networks in schizophrenia.We identified 32 feed-forward loops (FFLs) among our compiled schizophrenia-related miRNAs, TFs and genes. Our evaluation revealed that these observed FFLs were significantly enriched in schizophrenia genes. By converging the FFLs and mutual feedback loops, we constructed a novel miRNA-TF regulatory network for schizophrenia. Our analysis revealed EGR3 and hsa-miR-195 were core regulators in this regulatory network. We next proposed a model highlighting EGR3 and miRNAs involved in signaling pathways and regulatory networks in the nervous system. Finally, we suggested several single nucleotide polymorphisms (SNPs) located on miRNAs, their target sites, and TFBSs, which may have an effect in schizophrenia gene regulation.This study provides many insights on the regulatory mechanisms of genes involved in schizophrenia. It represents the first investigation of a miRNA-TF regulatory network for a complex disease, as demonstrated in schizophrenia.
| S-EPMC2834616 | biostudies-literature