scholarly journals Extensive NEUROG3 occupancy in the human pancreatic endocrine gene regulatory network

2021 ◽  
Author(s):  
Valérie Schreiber ◽  
Reuben Mercier ◽  
Sara Jímenez ◽  
Tao Ye ◽  
Emmanuel García-Sánchez ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Regulatory Network ◽  
Beta Cells ◽  
Regulatory Network ◽  
Islet Cell ◽  
Regulatory Elements ◽  
Cell Development ◽  
Bhlh Transcription Factor ◽  
Gene Regulatory ◽  
Endocrine Progenitors

Objective: Mice lacking the bHLH transcription factor (TF) Neurog3 do not form pancreatic islet cells, including insulin secreting beta cells, causing diabetes. In human, homozygous mutations of NEUROG3 manifest with neonatal or childhood diabetes. Despite this critical role in islet cell development, the precise function and downstream genetic programs regulated directly by NEUROG3 remain elusive. We therefore mapped genome-wide NEUROG3 occupancy in human induced pluripotent stem cell (iPSC)-derived endocrine progenitors and determined NEUROG3 dependency of associated genes to uncover direct targets. Methods: We generated a novel hiPSC line (NEUROG3-HA-P2A-Venus), where NEUROG3 is HA-tagged and fused to a self-cleaving fluorescent VENUS reporter. We used the CUT&RUN technique to map NEUROG3 occupancy and epigenetic marks in pancreatic endocrine progenitors (PEP) differentiated from this hiPSC line. We integrated NEUROG3 occupancy data with chromatin status and gene expression in PEPs and their NEUROG3-dependence. In addition, we searched whether NEUROG3 binds type 2 diabetes mellitus (T2DM)-associated variants at the PEP stage. Results: CUT&RUN revealed a total of 863 NEUROG3 binding sites assigned to 1268 unique genes. NEUROG3 occupancy was found at promoters as well as at distant cis-regulatory elements frequently overlapping within PEP active enhancers. De novo motif analyses defined a NEUROG3 consensus binding motif and suggested potential co-regulation of NEUROG3 target genes by FOXA, RFX or PBX transcription factors. Moreover, we found that 22% of the genes downregulated in NEUROG3−/− hESC-derived PEPs are bound by NEUROG3 and thus likely to be directly regulated. NEUROG3 targets include transcription factors known to have important roles in islet cell development or function, such as NEUROD1, PAX4, NKX2-2, SOX4, MLXIPL, LMX1B, RFX3, and NEUROG3 itself. Remarkably, we uncovered that NEUROG3 binds transcriptional regulator genes with enriched expression in human fetal pancreatic alpha (e.g., IRX1, IRX2), beta (e.g., NKX6-1, SMAD9, ISX, TFCP2L1) and delta cells (ERBB4) suggesting that NEUROG3 could control islets subtype programs. Moreover, NEUROG3 targets genes critical for insulin secretion in beta cells (e.g., GCK, ABCC8/KCNJ11, CACNA1A, CHGA, SCG2, SLC30A8 and PCSK1). In addition, we unveiled a panel of ncRNA potentially regulated by NEUROG3. Lastly, we identified several T2DM risk SNPs within NEUROG3 peaks suggesting a possible developmental role of NEUROG3 in T2DM susceptibility. Conclusion: Mapping of NEUROG3 genome occupancy in PEPs uncovers an unexpectedly broad, direct control of the endocrine gene regulatory network (GRN) and raises novel hypotheses on how this master regulator controls islet and beta cell differentiation.

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 Gene regulatory network analysis of Trichoderma reesei grown on glucose-lactose mixtures suggests links between development and cellulase production

2020 ◽  
Author(s):  
Aurélie Pirayre ◽  
Laurent Duval ◽  
Corinne Blugeon ◽  
Cyril Firmo ◽  
Sandrine Perrin ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Regulatory Network ◽  
Trichoderma Reesei ◽  
Regulatory Network ◽  
Cellulase Production ◽  
Biofuel Production ◽  
Batch Mode ◽  
Lactose Concentration ◽  
Gene Regulatory ◽  
The Impact

Abstract Background: The degradation of cellulose and hemicellulose molecules into simpler sugars such as glucose is part of the second generation biofuel production process. Hydrolysis of lignocellulosic substrates is usually performed by enzymes produced and secreted by the fungus Trichoderma reesei . Studies identifying transcription factors involved in the regulation of cellulase production have been conducted but no overview of the whole regulation network is available. A transcriptomic approach with mixtures of glucose and lactose, used as a substrate for cellulase induction, was used to help us decipher missing parts in the network.Results: Experimental results confirmed the impact of sugar mixture on the enzymatic cocktail composition. The transcriptomic study shows a temporal regulation of the main transcription factors and a lactose concentration impact on the transcriptional profile. A gene regulatory network built using the BRANE Cut software reveals three sub-networks related to i) a positive correlation between lactose concentration and cellulase production, ii) a particular dependence of the lactose onto the β-glucosidase regulation and iii) a negative regulation of the development process and growth.Conclusions: This work is the first investigating a transcriptomic study regarding the effects of pure and mixed carbon sources in a fed-batch mode. Our study expose a co-orchestration of xyr1 , clr2 and ace3 for cellulase and hemicellulase induction and production, a fine regulation of the β-glucosidase and a decrease of growth in favor of cellulase production. These conclusions provide us with potential targets for further genetic engineering leading to better cellulase-producing strains.

scholarly journals Tbx4 function during hindlimb development reveals a novel mechanism to explain the origins of proximal limb defects

Development ◽  
2021 ◽  
Author(s):  
Veronique Duboc ◽  
Fatima Sulaiman ◽  
Eleanor Feneck ◽  
Anna Kucharska ◽  
Donald Bell ◽  
...  
Keyword(s):  
Image Analysis ◽  
Transcription Factors ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Micromass Culture ◽  
Limb Defects ◽  
Limb Mesenchyme ◽  
Gene Regulatory ◽  
Live Image ◽  
Mesenchyme Cells

We dissect genetically a gene regulatory network, including the transcription factors Tbx4, Pitx1 and Isl1 that act cooperatively to establish the hindlimb bud and identify key differences in the pathways that initiate formation of the hindlimb and forelimb. Using live image analysis of limb mesenchyme cells undergoing chondrogenesis in micromass culture, we distinguish a series of changes in cellular behaviours and cohesiveness that are required for chondrogenic precursors to undergo differentiation. Furthermore, we provide evidence that the proximal hindlimb defects in the Tbx4 mutant result from a failure in the early differentiation step of chondroprogenitors into chondrocytes, providing a novel explanation for the origins of proximally-biased limb defects.

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 Retrotransposons spread potential cis-regulatory elements during mammary gland evolution

2019 ◽  
Author(s):  
Hidenori Nishihara
Keyword(s):  
Mammary Gland ◽  
Gene Regulatory Network ◽  
Binding Sites ◽  
Regulatory Network ◽  
Regulatory Elements ◽  
Estrogen Receptor Α ◽  
Endogenous Retrovirus ◽  
Cis Elements ◽  
Binding Motifs ◽  
Gene Regulatory

Abstract Acquisition of cis-elements is a major driving force for rewiring a gene regulatory network. Several kinds of transposable elements (TEs), mostly retrotransposons that propagate via a copy-and-paste mechanism, are known to possess transcription factor binding motifs and have provided source sequences for enhancers/promoters. However, it remains largely unknown whether retrotransposons have spread the binding sites of master regulators of morphogenesis and accelerated cis-regulatory expansion involved in common mammalian morphological features during evolution. Here, I demonstrate that thousands of binding sites for estrogen receptor α (ERα) and three related pioneer factors (FoxA1, GATA3 and AP2γ) that are essential regulators of mammary gland development arose from a spreading of the binding motifs by retrotransposons. The TE-derived functional elements serve primarily as distal enhancers and are enriched around genes associated with mammary gland morphogenesis. The source TEs occurred via a two-phased expansion consisting of mainly L2/MIR in a eutherian ancestor and endogenous retrovirus 1 (ERV1) in simian primates and murines. Thus the build-up of potential sources for cis-elements by retrotransposons followed by their frequent utilization by the host (co-option/exaptation) may have a general accelerating effect on both establishing and diversifying a gene regulatory network, leading to morphological innovation.

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