scholarly journals Absolute quantification of transcription factors reveals principles of gene regulation in erythropoiesis

2019 ◽  
Author(s):  
Mark A. Gillespie ◽  
Carmen G. Palii ◽  
Daniel Sanchez-Taltavull ◽  
Paul Shannon ◽  
William J.R. Longabaugh ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Cell Fate ◽  
Regulatory Network ◽  
Copy Number ◽  
Absolute Quantification ◽  
Cellular Processes ◽  
Gene Regulatory ◽  
Surprising Discovery

SummaryDynamic cellular processes such as differentiation are driven by changes in the abundances of transcription factors (TFs). Yet, despite years of studies we still do not know the protein copy number of TFs in the nucleus. 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, corepressors are dramatically more abundant than coactivators at the protein, 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.

scholarly journals A developmental gene regulatory network for invasive differentiation of theC. elegansanchor cell

2019 ◽  
Author(s):  
Taylor N. Medwig-Kinney ◽  
Jayson J. Smith ◽  
Nicholas J. Palmisano ◽  
Sujata Tank ◽  
Wan Zhang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Regulatory Network ◽  
Cell Fate ◽  
Regulatory Network ◽  
Cell Biology ◽  
Type I ◽  
Cell Specification ◽  
C Elegans ◽  
Gene Regulatory ◽  
Anchor Cell

ABSTRACTCellular invasion is a key part of development, immunity, and disease. Using thein vivomodel ofC. elegansanchor cell invasion, we characterize the gene regulatory network that promotes invasive differentiation. The anchor cell is initially specified in a stochastic cell fate decision mediated by Notch signaling. Previous research has identified four conserved transcription factors,fos-1a(Fos),egl-43(EVI1/MEL),hlh-2(E/Daughterless) andnhr-67(NR2E1/TLX), that mediate anchor cell specification and/or invasive differentiation. Connections between these transcription factors and the underlying cell biology that they regulate is poorly understood. Here, using genome editing and RNA interference, we examine transcription factor interactions prior to and after anchor cell specification. During invasion we identify thategl-43,hlh-2, andnhr-67function together in a type I coherent feed-forward loop with positive feedback. Conversely, prior to specification, these transcription factors function independent of one another to regulate LIN-12 (Notch) activity. Together, these results demonstrate that, although the same transcription factors can function in fate specification and differentiated cell behavior, a gene regulatory network can be rapidly re-wired to reinforce a post-mitotic, pro-invasive state.SUMMARY STATEMENTBasement membrane invasion by theC. elegansanchor cell is coordinated by a dynamic gene regulatory network encompassing cell cycle dependent and independent sub-circuits.

scholarly journals Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

2017 ◽  
Vol 114 (23) ◽  
pp. 5800-5807 ◽  
Author(s):  
William J. R. Longabaugh ◽  
Weihua Zeng ◽  
Jingli A. Zhang ◽  
Hiroyuki Hosokawa ◽  
Camden S. Jansen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Notch Signaling ◽  
Gene Regulatory Network ◽  
Cell Fate ◽  
Regulatory Network ◽  
T Cell Development ◽  
Cell Specification ◽  
Gene Regulatory

T-cell development from hematopoietic progenitors depends on multiple transcription factors, mobilized and modulated by intrathymic Notch signaling. Key aspects of T-cell specification network architecture have been illuminated through recent reports defining roles of transcription factors PU.1, GATA-3, and E2A, their interactions with Notch signaling, and roles of Runx1, TCF-1, and Hes1, providing bases for a comprehensively updated model of the T-cell specification gene regulatory network presented herein. However, the role of lineage commitment factor Bcl11b has been unclear. We use self-organizing maps on 63 RNA-seq datasets from normal and perturbed T-cell development to identify functional targets of Bcl11b during commitment and relate them to other regulomes. We show that both activation and repression target genes can be bound by Bcl11b in vivo, and that Bcl11b effects overlap with E2A-dependent effects. The newly clarified role of Bcl11b distinguishes discrete components of commitment, resolving how innate lymphoid, myeloid, and dendritic, and B-cell fate alternatives are excluded by different mechanisms.

Super-Enhancer-Associated Transcription Factors Maintain Transcriptional Regulation in Mature Podocytes

2021 ◽  
pp. ASN.2020081177
Author(s):  
Jingping Yang ◽  
Difei Zhang ◽  
Masaru Motojima ◽  
Tsutomu Kume ◽  
Qing Hou ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Animal Models ◽  
Cell Fate ◽  
Control Cell ◽  
Transgenic Animal ◽  
Animal Models Of Disease ◽  
Super Enhancer ◽  
Models Of Disease ◽  
Human Glomerulus

BackgroundTranscriptional programs control cell fate, and identifying their components is critical for understanding diseases caused by cell lesion, such as podocytopathy. Although many transcription factors (TFs) are necessary for cell-state maintenance in glomeruli, their roles in transcriptional regulation are not well understood.MethodsThe distribution of H3K27ac histones in human glomerulus cells was analyzed to identify superenhancer-associated TFs, and ChIP-seq and transcriptomics were performed to elucidate the regulatory roles of the TFs. Transgenic animal models of disease were further investigated to confirm the roles of specific TFs in podocyte maintenance.ResultsSuperenhancer distribution revealed a group of potential TFs in core regulatory circuits in human glomerulus cells, including FOXC1/2, WT1, and LMX1B. Integration of transcriptome and cistrome data of FOXC1/2 in mice resolved transcriptional regulation in podocyte maintenance. FOXC1/2 regulated differentiation-associated transcription in mature podocytes. In both humans and animal models, mature podocyte injury was accompanied by deregulation of FOXC1/2 expression, and FOXC1/2 overexpression could protect podocytes in zebrafish.ConclusionsFOXC1/2 maintain podocyte differentiation through transcriptional stabilization. The genome-wide chromatin resources support further investigation of TFs’ regulatory roles in glomeruli transcription programs.

scholarly journals Identification of Transcription Factors Regulating Senescence in Wheat through Gene Regulatory Network Modelling

2019 ◽  
Vol 180 (3) ◽  
pp. 1740-1755 ◽  
Author(s):  
Philippa Borrill ◽  
Sophie A. Harrington ◽  
James Simmonds ◽  
Cristobal Uauy
Keyword(s):  
Transcription Factors ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Network Modelling ◽  
Gene Regulatory

scholarly journals The identification of transcription factors expressed in the notochord of Ciona intestinalis adds new potential players to the brachyury gene regulatory network

2011 ◽  
Vol 240 (9) ◽  
pp. spcone-spcone
Author(s):  
Diana S. José-Edwards ◽  
Pierre Kerner ◽  
Jamie E. Kugler ◽  
Wei Deng ◽  
Di Jiang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Ciona Intestinalis ◽  
Gene Regulatory

scholarly journals Identification of transcription factors regulating senescence in wheat through gene regulatory network modelling

2018 ◽  
Author(s):  
Philippa Borrill ◽  
Sophie A. Harrington ◽  
James Simmonds ◽  
Cristobal Uauy
Keyword(s):  
Transcription Factors ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Time Series Data ◽  
Nutrient Content ◽  
Series Data ◽  
Network Modelling ◽  
Polyploid Wheat ◽  
Gene Regulatory ◽  
Developmental Programme

AbstractSenescence is a tightly regulated developmental programme which is coordinated by transcription factors. Identifying these transcription factors in crops will provide opportunities to tailor the senescence process to different environmental conditions and regulate the balance between yield and grain nutrient content. Here we use ten time points of gene expression data alongside gene network modelling to identify transcription factors regulating senescence in polyploid wheat. We observe two main phases of transcription changes during senescence: early downregulation of housekeeping and metabolic processes followed by upregulation of transport and hormone related genes. We have identified transcription factor families associated with these early and later waves of differential expression. Using gene regulatory network modelling alongside complementary publicly available datasets we identified candidate transcription factors for controlling senescence. We validated the function of one of these candidate transcription factors in senescence using wheat chemically-induced mutants. This study lays the ground work to understand the transcription factors which regulate senescence in polyploid wheat and exemplifies the integration of time-series data with publicly available expression atlases and networks to identify candidate regulatory genes.

scholarly journals A GO catalogue of human DNA-binding transcription factors

2020 ◽  
Author(s):  
Ruth C. Lovering ◽  
Pascale Gaudet ◽  
Marcio L. Acencio ◽  
Alex Ignatchenko ◽  
Arttu Jolma ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Transcription Factors ◽  
Dna Binding ◽  
Regulation Of Transcription ◽  
Sequence Motifs ◽  
Specific Sequence ◽  
Go Annotation ◽  
Human Dna ◽  
Gene Regulatory ◽  
The Many

AbstractDNA-binding transcription factors recognise genomic addresses, specific sequence motifs in gene regulatory regions, to control gene transcription. A complete and reliable catalogue of all DNA-binding transcription factors is key to investigating the delicate balance of gene regulation in response to environmental and developmental stimuli. The need for such a catalogue of proteins is demonstrated by the many lists of DNA-binding transcription factors that have been produced over the past decade.The COST Action Gene Regulation Ensemble Effort for the Knowledge Commons (GREEKC) Consortium brought together experts in the field of transcription with the aim of providing high quality and interoperable gene regulatory data. The Gene Ontology (GO) Consortium provides strict definitions for gene product function, including factors that regulate transcription. The collaboration between the GREEKC and GO Consortia has enabled the application of those definitions to produce a new curated catalogue of human DNA-binding transcription factors, that can be accessed at https://www.ebi.ac.uk/QuickGO/targetset/dbTF.In addition, this curation effort has led to the GO annotation of almost sixty thousand DNA-binding transcription factors in over a hundred species. Thus, this work will aid researchers investigating the regulation of transcription in both biomedical and basic science.

scholarly journals Formalizing metabolic-regulatory networks by hybrid automata

2019 ◽  
Author(s):  
Lin Liu ◽  
Alexander Bockmayr
Keyword(s):  
Transcriptional Regulation ◽  
Regulatory Network ◽  
Regulatory Networks ◽  
Discrete Control ◽  
Hybrid Automata ◽  
Hybrid Automaton ◽  
Metabolic System ◽  
Computational Approaches ◽  
Cellular Processes ◽  
Dynamic Interplay

AbstractComputational approaches in systems biology have become a powerful tool for understanding the fundamental mechanisms of cellular metabolism and regulation. However, the interplay between the regulatory and the metabolic system is still poorly understood. In particular, there is a need for formal mathematical frameworks that allow analyzing metabolism together with dynamic enzyme resources and regulatory events. Here, we introduce a metabolic-regulatory network model (MRN) that allows integrating metabolism with transcriptional regulation, macromolecule production and enzyme resources. Using this model, we show that the dynamic interplay between these different cellular processes can be formalized by a hybrid automaton, combining continuous dynamics and discrete control.

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