scholarly journals scRNA-Sequencing uncovers a TCF4-dependent transcription factor network regulating commissure development

Development ◽  
2021 ◽  
Author(s):  
Marie-Theres Wittmann ◽  
Sayako Katada ◽  
Elisabeth Sock ◽  
Philipp Kirchner ◽  
Arif B. Ekici ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activity ◽  
Projection Neurons ◽  
Bhlh Transcription Factor ◽  
Sequencing Data ◽  
Functional Interaction ◽  
Interhemispheric Connectivity ◽  
Identify Transcription Factor ◽  
Transcription Factor 4

Transcription factor 4 (TCF4) is a critical regulator of neurodevelopment and has been linked to the pathogenesis of autism, intellectual disability, and schizophrenia. As a class I bHLH transcription factor it is assumed that TCF4 exerts its neurodevelopmental functions through dimerization with proneural class II bHLH TFs. Here, we aim to identify transcription factor (TF) partners of TCF4 in the control of interhemispheric connectivity formation. Using a new bioinformatic strategy integrating TF expression levels and regulon activities from single cell RNA-sequencing data, we find evidence that TCF4 interacts with non-bHLH TFs and modulates their transcriptional activity in Satb2+ intercortical projection neurons. Notably, this network comprises regulators linked to the pathogenesis of neurodevelopmental disorders, e.g. FOXG1, SOX11 and BRG1. In support of the functional interaction of TCF4 with non-bHLH TFs we find that TCF4 and SOX11 biochemically interact and cooperatively control commissure formation in vivo, and regulate the transcription of genes implied in this process. Next to identifying new candidate interactors of TCF4 in neurodevelopment, this study illustrates how scRNA-Seq data can be leveraged to predict TFs networks in neurodevelopmental processes.

scholarly journals scRNA-Sequencing uncovers a TCF-4-dependent transcription factor network regulating commissure development

2020 ◽  
Author(s):  
Marie-Theres Wittmann ◽  
Philipp Kirchner ◽  
Arif B. Ekici ◽  
Elisabeth Sock ◽  
D. Chichung Lie ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Projection Neurons ◽  
Sequencing Data ◽  
Transcription Factor Network ◽  
Brain Functions ◽  
Interhemispheric Connectivity ◽  
Transcription Factor Expression

AbstractIntercortical connectivity is important for higher cognitive brain functions by providing the basis for integrating information from both hemispheres. We show that ablation of the neurodevelopmental disorder associated bHLH factor Tcf4 results in complete loss of forebrain commissural systems in mice. Applying a new bioinformatic strategy integrating transcription factor expression levels and regulon activities from single cell RNA-sequencing data predicted a TCF-4 interacting transcription factor network in intercortical projection neurons regulating commissure formation. This network comprises a number of regulators previously linked to the pathogenesis of intellectual disability, autism-spectrum disorders and schizophrenia, e.g. Foxg1, Sox11 and Brg1. Furthermore, we demonstrate that TCF-4 and SOX11 biochemically interact and cooperatively control commissure formation in vivo, and regulate the transcription of genes implied in this process. Our study provides a regulatory transcriptional network for the development of interhemispheric connectivity with potential pathophysiological relevance in neurodevelopmental disorders.

The basic helix-loop-helix transcription factor bHLH95 affects fruit ripening and multiple metabolisms in tomato

2020 ◽  
Vol 71 (20) ◽  
pp. 6311-6327
Author(s):  
Lincheng Zhang ◽  
Jing Kang ◽  
Qiaoli Xie ◽  
Jun Gong ◽  
Hui Shen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fruit Ripening ◽  
Tomato Fruit ◽  
Soluble Sugar ◽  
Glutathione Metabolism ◽  
Bhlh Transcription Factor ◽  
Total Carotenoids ◽  
Helix Loop Helix ◽  
Tomato Fruit Ripening

Abstract Ethylene signaling pathways regulate several physiological alterations that occur during tomato fruit ripening, such as changes in colour and flavour. The mechanisms underlying the transcriptional regulation of genes in these pathways remain unclear, although the role of the MADS-box transcription factor RIN has been widely reported. Here, we describe a bHLH transcription factor, SlbHLH95, whose transcripts accumulated abundantly in breaker+4 and breaker+7 fruits compared with rin (ripening inhibitor) and Nr (never ripe) mutants. Moreover, the promoter activity of SlbHLH95 was regulated by RIN in vivo. Suppression of SlbHLH95 resulted in reduced sensitivity to ethylene, decreased accumulation of total carotenoids, and lowered glutathione content, and inhibited the expression of fruit ripening- and glutathione metabolism-related genes. Conversely, up-regulation of SlbHLH95 in wild-type tomato resulted in higher sensitivity to ethylene, increased accumulation of total carotenoids, slightly premature ripening, and elevated accumulation of glutathione, soluble sugar, and starch. Notably, overexpression of SlbHLH95 in rin led to the up-regulated expression of fruit ripening-related genes (FUL1, FUL2, SAUR69, ERF4, and CNR) and multiple glutathione metabolism-related genes (GSH1, GSH2, GSTF1, and GSTF5). These results clarified that SlbHLH95 participates in the regulation of fruit ripening and affects ethylene sensitivity and multiple metabolisms targeted by RIN in tomato.

scholarly journals Parathyroid Hormone Increases Activating Transcription Factor 4 Expression and Activity in Osteoblasts: Requirement for Osteocalcin Gene Expression

Endocrinology ◽  
2008 ◽  
Vol 149 (4) ◽  
pp. 1960-1968 ◽  
Author(s):  
Shibing Yu ◽  
Renny T. Franceschi ◽  
Min Luo ◽  
Xiaoyan Zhang ◽  
Di Jiang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Kinase ◽  
Transcriptional Activity ◽  
De Novo ◽  
Dependent Manner ◽  
Specific Element ◽  
Activating Transcription Factor 4 ◽  
Activating Transcription Factor ◽  
Transcription Factor 4 ◽  
Expression And Activity

PTH is an important peptide hormone regulator of calcium homeostasis and osteoblast function. However, its mechanism of action in osteoblasts is poorly understood. Our previous study demonstrated that PTH activates mouse osteocalcin (Ocn) gene 2 promoter through the osteoblast-specific element 1 site, a recently identified activating transcription factor-4 (ATF4) -binding element. In the present study, we examined effects of PTH on ATF4 expression and activity as well as the requirement for ATF4 in the regulation of Ocn by PTH. Results show that PTH elevated levels of ATF4 mRNA and protein in a dose- and time-dependent manner. This PTH regulation requires transcriptional activity but not de novo protein synthesis. PTH also increased binding of nuclear extracts to osteoblast-specific element 1 DNA. PTH stimulated ATF4-dependent transcriptional activity mainly through protein kinase A with a lesser requirement for protein kinase C and MAPK/ERK pathways. Lastly, PTH stimulation of Ocn expression was lost by small interfering RNA down-regulation of ATF4 in MC-4 cells and Atf4−/− bone marrow stromal cells. Collectively, these studies for the first time demonstrate that PTH increases ATF4 expression and activity and that ATF4 is required for PTH induction of Ocn expression in osteoblasts.

scholarly journals Regulation of MEF2 by Histone Deacetylase 4- and SIRT1 Deacetylase-Mediated Lysine Modifications

2005 ◽  
Vol 25 (19) ◽  
pp. 8456-8464 ◽  
Author(s):  
Xuan Zhao ◽  
Thomas Sternsdorf ◽  
Timothy A. Bolger ◽  
Ronald M. Evans ◽  
Tso-Pang Yao
Keyword(s):  
Transcription Factor ◽  
Histone Deacetylase ◽  
Transcriptional Activity ◽  
Histone Deacetylation ◽  
Muscle Cell Differentiation ◽  
Histone Deacetylase 4 ◽  
Reconstituted System ◽  
Sumo E3 Ligase

ABSTRACT The class II deacetylase histone deacetylase 4 (HDAC4) negatively regulates the transcription factor MEF2. HDAC4 is believed to repress MEF2 transcriptional activity by binding to MEF2 and catalyzing local histone deacetylation. Here we report that HDAC4 also controls MEF2 by a novel SUMO E3 ligase activity. We show that HDAC4 interacts with the SUMO E2 conjugating enzyme Ubc9 and is itself sumoylated. The overexpression of HDAC4 leads to prominent MEF2 sumoylation in vivo, whereas recombinant HDAC4 stimulates MEF2 sumoylation in a reconstituted system in vitro. Importantly, HDAC4 promotes sumoylation on a lysine residue that is also subject to acetylation by a MEF2 coactivator, the acetyltransferase CBP, suggesting a possible interplay between acetylation and sumoylation in regulating MEF2 activity. Indeed, MEF2 acetylation is correlated with MEF2 activation and dynamically induced upon muscle cell differentiation, while sumoylation inhibits MEF2 transcriptional activity. Unexpectedly, we found that HDAC4 does not function as a MEF2 deacetylase. Instead, the NAD+-dependent deacetylase SIRT1 can potently induce MEF2 deacetylation. Our studies reveal a novel regulation of MEF2 transcriptional activity by two distinct classes of deacetylases that affect MEF2 sumoylation and acetylation.

scholarly journals Phosphorylation of MafA Is Essential for Its Transcriptional and Biological Properties

2001 ◽  
Vol 21 (14) ◽  
pp. 4441-4452 ◽  
Author(s):  
Sofia Benkhelifa ◽  
Sylvain Provot ◽  
Eugène Nabais ◽  
Alain Eychène ◽  
Georges Calothy ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activity ◽  
Leucine Zipper ◽  
Biological Properties ◽  
Erk Pathway ◽  
Mitogen Activated Protein Kinases ◽  
Mitogen Activated Protein ◽  
Basic Region

ABSTRACT We previously described the identification of quail MafA, a novel transcription factor of the Maf bZIP (basic region leucine zipper) family, expressed in the differentiating neuroretina (NR). In the present study, we provide the first evidence that MafA is phosphorylated and that its biological properties strongly rely upon phosphorylation of serines 14 and 65, two residues located in the transcriptional activating domain within a consensus for phosphorylation by mitogen-activated protein kinases and which are conserved among Maf proteins. These residues are phosphorylated by ERK2 but not by p38, JNK, and ERK5 in vitro. However, the contribution of the MEK/ERK pathway to MafA phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs MafA capacity to activate transcription. Furthermore, we show that the MafA S14A/S65A mutant displays reduced capacity to induce expression of QR1, an NR-specific target of Maf proteins. Likewise, the integrity of serines 14 and 65 is essential for the MafA ability to stimulate expression of crystallin genes in NR cells and to induce NR-to-lens transdifferentiation. Thus, the MafA capacity to induce differentiation programs is dependent on its phosphorylation.

scholarly journals Studies on the Role of the Transcription Factor Tcf21 in the Transdifferentiation of Parietal Epithelial Cells into Podocyte-Like Cells

2021 ◽  
Vol 55 (S4) ◽  
pp. 48-67
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Epithelial Cells ◽  
Bhlh Transcription Factor ◽  
Binding Motif ◽  
A Genome ◽  
Parietal Epithelial Cells ◽  
Transcription Factor Yy1

Background/Aims: Podocyte differentiation is essential for proper blood filtration in the kidney. It is well known that transcription factors play an essential role to maintain the differentiation of podocytes. The present study is focused on the basic helix-loop-helix (bHLH) transcription factor Tcf21 (Pod1) which is essential for the development of podocytes in vivo. Since parietal epithelial cells (PECs) are still under debate to be progenitor cells which can differentiate into podocytes, we wanted to find out whether the expression of Tcf21 induces a transition of PECs into podocytes. Methods: We transfected PECs with Tcf21-GFP and analyzed the expression of PEC- and podocyte-specific markers. Furthermore, we performed ChIP-Seq analysis to identify new putative interaction partners and target genes of Tcf21. Results: By gene arrays analysis, we found that podocytes express high levels of Tcf21 in vivo in contrast to cultured podocytes and parietal epithelial cells (PECs) in vitro. After the expression of Tcf21 in PECs, we observed a downregulation of specific PEC markers like caveolin‑1, β-catenin and Pax2. Additionally, we found that the upregulation of Tcf21 induced multi-lobulation of cell nuclei, budding and a formation of micronuclei (MBM). Furthermore, a high number of PECs showed a tetraploid set of chromosomes. By qRT-PCR and Western blot analysis, we revealed that the transcription factor YY1 is downregulated by Tcf21. Interestingly, co-expression of YY1 and Tcf21 rescues MBM and reduced tetraploidy. By ChIP-Seq analysis, we identified a genome-wide Tcf21-binding site (CAGCTG), which matched the CANNTG sequence, a common E-box binding motif used by bHLH transcription factors. Using this technique, we identified additional Tcf21 targets genes that are involved in the regulation of the cell cycle (e.g. Mdm2, Cdc45, Cyclin D1, Cyclin D2), on the stability of microtubules (e.g. Mapt) as well as chromosome segregation. Conclusion: Taken together, we demonstrate that Tcf21 inhibits the expression of PEC-specific markers and of the transcription factor YY1, induces MBM as well as regulates the cell cycle suggesting that Tcf21 might be important for PEC differentiation into podocyte-like cells.

scholarly journals The IRE1a-XBP1 pathway promotes T helper cell differentiation by resolving secretory stress and accelerating proliferation

2017 ◽  
Author(s):  
Jhuma Pramanik ◽  
Xi Chen ◽  
Gozde Kar ◽  
Tomás Gomes ◽  
Johan Henriksson ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Lymphocyte Activation ◽  
Cell Types ◽  
T Helper Cell ◽  
Helper Cell ◽  
Secretory Cells ◽  
T Helper ◽  
Sequencing Data

SummaryThe IRE1a-XBP1 pathway, a conserved adaptive mediator of the unfolded protein response, is indispensable for the development of secretory cells. It maintains endoplasmic reticulum homeostasis by facilitating protein folding and enhancing secretory capacity of the cells. Its role in immune cells is emerging. It is involved in dendritic cell, plasma cell and eosinophil development and differentiation. Using genome-wide approaches, integrating ChIPmentation and mRNA-sequencing data, we have elucidated the regulatory circuitry governed by the IRE1a-XBP1 pathway in type-2 T helper cells (Th2). We show that the XBP1 transcription factor is activated by splicing in vivo in T helper cell lineages. We report a comprehensive repertoire of XBP1 target genes in Th2 lymphocytes. We found that the pathway is conserved across cell types in terms of resolving secretory stress, and has T helper cell-specific functions in controlling activation-dependent Th2 cell proliferation and regulating cytokine expression in addition to secretion. These results provide a detailed picture of the regulatory map governed by the XBP1 transcription factor during Th2 lymphocyte activation.

scholarly journals TFIIA Interacts with TFIID via Association with TATA-Binding Protein and TAF40

2001 ◽  
Vol 21 (5) ◽  
pp. 1737-1746 ◽  
Author(s):  
Susan M. Kraemer ◽  
Ryan T. Ranallo ◽  
Ryan C. Ogg ◽  
Laurie A. Stargell
Keyword(s):  
Transcription Factor ◽  
Rna Polymerase Ii ◽  
Functional Role ◽  
Associated Factors ◽  
Binding Protein ◽  
Tata Binding Protein ◽  
Functional Interaction ◽  
General Transcription Factor ◽  
Tata Element

ABSTRACT TFIIA and TATA-binding protein (TBP) associate directly at the TATA element of genes transcribed by RNA polymerase II. In vivo, TBP is complexed with approximately 14 TBP-associated factors (TAFs) to form the general transcription factor TFIID. How TFIIA and TFIID communicate is not well understood. We show that in addition to making direct contacts with TBP, yeast TAF40 interacts directly and specifically with TFIIA. Mutational analyses of the Toa2 subunit of TFIIA indicate that loss of functional interaction between TFIIA and TAF40 results in conditional growth phenotypes and defects in transcription. These results demonstrate that the TFIIA-TAF40 interaction is important in vivo and indicate a functional role for TAF40 as a bridging factor between TFIIA and TFIID.

Delta-lactoferrin, an intracellular lactoferrin isoform that acts as a transcription factor1This article is part of a Special Issue entitled Lactoferrin and has undergone the Journal's usual peer review process.

2012 ◽  
Vol 90 (3) ◽  
pp. 307-319 ◽  
Author(s):  
Christophe Mariller ◽  
Stephan Hardivillé ◽  
Esthelle Hoedt ◽  
Isabelle Huvent ◽  
Socorro Pina-Canseco ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Posttranslational Modifications ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Peer Review Process ◽  
Good Prognosis ◽  
Cycle Arrest ◽  
Fine Regulation ◽  
Tissue Marker

Delta-lactoferrin (ΔLf) is a transcription factor of which the expression is downregulated in cancer. It is a healthy tissue marker and a high expression level of its transcripts was correlated with a good prognosis in breast cancer. ΔLf results from alternative promoter usage of the hLf gene leading to the production of 2 isoforms with alternative N-termini: lactoferrin, which is secreted, and ΔLf, its nucleocytoplasmic counterpart. ΔLf possesses antiproliferative properties and induces cell cycle arrest. It is an efficient transcription factor interacting in vivo via a ΔLf response element found in the Skp1, Bax, DcpS, and SelH promoters. Since ΔLf possesses different target genes, modifications in its activity or concentration may have crucial effects on cell homeostasis. Posttranslational modifications modulate ΔLf transcription factor activity. Our earlier investigations showed that O-GlcNAcylation negatively regulates ΔLf transcriptional activity, whilst inhibiting its ubiquitination and increasing its half-life. On the other hand, phosphorylation potentiates ΔLf transcriptional activity. Recently, we showed that ΔLf is also modified by SUMOylation. Therefore, cooperation and (or) competition among SUMOylation, ubiquitination, phosphorylation, and O-GlcNAcylation may contribute to the establishment of a fine regulation of ΔLf transcriptional activity depending on the type of target gene and cellular homeostasis.

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