scholarly journals Selective Requirement for Polycomb Repressor Complex 2 in the Generation of Specific Hypothalamic Neuronal Sub-types

2021 ◽  
Author(s):  
Stefan S Thor ◽  
Behzad Yaghmaeian Salmani ◽  
Brad Balderson ◽  
Susanne Bauer ◽  
Helen Ekman ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Ectopic Expression ◽  
Signalling Pathways ◽  
Homeotic Genes ◽  
Loss Reduction ◽  
Double Positive ◽  
Repressor Complex ◽  
Gene Regulatory ◽  
Cell Cycle Inhibitors

The hypothalamus displays staggering cellular diversity, chiefly established during embryogenesis by the interplay of several signalling pathways and a battery of transcription factors. However, the contribution of epigenetic cues to hypothalamus development remains unclear. We mutated the Polycomb Repressor Complex 2 gene Eed in the developing mouse hypothalamus, which resulted in the loss of H3K27me3; a fundamental epigenetic repressor mark. This triggered ectopic expression of posteriorly expressed regulators (e.g., Hox homeotic genes), upregulation of cell cycle inhibitors and reduced proliferation. Surprisingly, despite these effects, single cell transcriptomic analysis revealed that the majority of neuronal subtypes were still generated in Eed mutants. However, we observed an increase in Glutamatergic/GABAergic double-positive cells, as well as loss/reduction of dopamine, Hypocretin/Orexin and Tac2 neurons. These findings indicate that many aspects of the hypothalamic gene regulatory flow can proceed without the key H3K27me3 epigenetic repressor mark, and points to a unique sensitivity of particular neuronal sub-types to a disrupted epigenomic landscape.

scholarly journals Cell Cycle Inhibition by FoxO Forkhead Transcription Factors Involves Downregulation of Cyclin D

2002 ◽  
Vol 22 (22) ◽  
pp. 7842-7852 ◽  
Author(s):  
Marc Schmidt ◽  
Sylvia Fernandez de Mattos ◽  
Armando van der Horst ◽  
Rob Klompmaker ◽  
Geert J. P. L Kops ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Protein Expression ◽  
Cell Cycle Arrest ◽  
Cellular Proliferation ◽  
Kinase Inhibitor ◽  
Ectopic Expression ◽  
Forkhead Transcription Factors ◽  
Cycle Arrest ◽  
Cell Cycle Inhibition

ABSTRACT The FoxO forkhead transcription factors FoxO4 (AFX), FoxO3a (FKHR.L1), and FoxO1a (FKHR) represent important physiological targets of phosphatidylinositol-3 kinase (PI3K)/protein kinase B (PKB) signaling. Overexpression or conditional activation of FoxO factors is able to antagonize many responses to constitutive PI3K/PKB activation including its effect on cellular proliferation. It was previously shown that the FoxO-induced cell cycle arrest is partially mediated by enhanced transcription and protein expression of the cyclin-dependent kinase inhibitor p27kip1 (R. H. Medema, G. J. Kops, J. L. Bos, and B. M. Burgering, Nature 404:782-787, 2000). Here we have identified a p27kip1-independent mechanism that plays an important role in the antiproliferative effect of FoxO factors. Forced expression or conditional activation of FoxO factors leads to reduced protein expression of the D-type cyclins D1 and D2 and is associated with an impaired capacity of CDK4 to phosphorylate and inactivate the S-phase repressor pRb. Downregulation of D-type cyclins involves a transcriptional repression mechanism and does not require p27kip1 function. Ectopic expression of cyclin D1 can partially overcome FoxO factor-induced cell cycle arrest, demonstrating that downregulation of D-type cyclins represents a physiologically relevant mechanism of FoxO-induced cell cycle inhibition.

scholarly journals Evolution of master sex determiners: TGF-β signalling pathways at regulatory crossroads

2021 ◽  
Vol 376 (1832) ◽  
pp. 20200091 ◽  
Author(s):  
Qiaowei Pan ◽  
Tomas Kay ◽  
Alexandra Depincé ◽  
Mateus Adolfi ◽  
Manfred Schartl ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Sex Chromosomes ◽  
Regulatory Network ◽  
Chromosome Evolution ◽  
Sex Chromosome ◽  
Signalling Pathway ◽  
Signalling Pathways ◽  
Sex Chromosome Evolution ◽  
Theme Issue ◽  
Gene Regulatory

To date, more than 20 different vertebrate master sex-determining genes have been identified on different sex chromosomes of mammals, birds, frogs and fish. Interestingly, six of these genes are transcription factors ( Dmrt1 - or Sox3 - related) and 13 others belong to the TGF-β signalling pathway ( Amh , Amhr2 , Bmpr1b , Gsdf and Gdf6 ). This pattern suggests that only a limited group of factors/signalling pathways are prone to become top regulators again and again. Although being clearly a subordinate member of the sex-regulatory network in mammals, the TGF-β signalling pathway made it to the top recurrently and independently. Facing this rolling wave of TGF-β signalling pathways, this review will decipher how the TGF-β signalling pathways cope with the canonical sex gene regulatory network and challenge the current evolutionary concepts accounting for the diversity of sex-determining mechanisms. This article is part of the theme issue ‘Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part I)’.

scholarly journals Regulation of transcription reactivation dynamics exiting mitosis

2021 ◽  
Vol 17 (10) ◽  
pp. e1009354
Author(s):  
Sergio Sarnataro ◽  
Andrea Riba ◽  
Nacho Molina
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Control Cell ◽  
Core Gene ◽  
Regulation Of Transcription ◽  
Gene Regulatory

Proliferating cells experience a global reduction of transcription during mitosis, yet their cell identity is maintained and regulatory information is propagated from mother to daughter cells. Mitotic bookmarking by transcription factors has been proposed as a potential mechanism to ensure the reactivation of transcription at the proper set of genes exiting mitosis. Recently, mitotic transcription and waves of transcription reactivation have been observed in synchronized populations of human hepatoma cells. However, the study did not consider that mitotic-arrested cell populations progressively desynchronize leading to measurements of gene expression on a mixture of cells at different internal cell-cycle times. Moreover, it is not well understood yet what is the precise role of mitotic bookmarking on mitotic transcription as well as on the transcription reactivation waves. Ultimately, the core gene regulatory network driving the precise transcription reactivation dynamics remains to be identified. To address these questions, we developed a mathematical model to correct for the progressive desynchronization of cells and estimate gene expression dynamics with respect to a cell-cycle pseudotime. Furthermore, we used a multiple linear regression model to infer transcription factor activity dynamics. Our analysis allows us to characterize waves of transcription factor activities exiting mitosis and predict a core gene regulatory network responsible of the transcription reactivation dynamics. Moreover, we identified more than 60 transcription factors that are highly active during mitosis and represent new candidates of mitotic bookmarking factors which could be relevant therapeutic targets to control cell proliferation.

scholarly journals Two transcription factors, Pou4f2 and Isl1, are sufficient to specify the retinal ganglion cell fate

2015 ◽  
Vol 112 (13) ◽  
pp. E1559-E1568 ◽  
Author(s):  
Fuguo Wu ◽  
Tadeusz J. Kaczynski ◽  
Santhosh Sethuramanujam ◽  
Renzhong Li ◽  
Varsha Jain ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Ganglion Cells ◽  
Ectopic Expression ◽  
Cell Types ◽  
Retinal Cell ◽  
Retinal Ganglion ◽  
Pou Domain ◽  
Gene Enhancer ◽  
Gene Regulatory

As with other retinal cell types, retinal ganglion cells (RGCs) arise from multipotent retinal progenitor cells (RPCs), and their formation is regulated by a hierarchical gene-regulatory network (GRN). Within this GRN, three transcription factors—atonal homolog 7 (Atoh7), POU domain, class 4, transcription factor 2 (Pou4f2), and insulin gene enhancer protein 1 (Isl1)—occupy key node positions at two different stages of RGC development. Atoh7 is upstream and is required for RPCs to gain competence for an RGC fate, whereas Pou4f2 and Isl1 are downstream and regulate RGC differentiation. However, the genetic and molecular basis for the specification of the RGC fate, a key step in RGC development, remains unclear. Here we report that ectopic expression of Pou4f2 and Isl1 in the Atoh7-null retina using a binary knockin-transgenic system is sufficient for the specification of the RGC fate. The RGCs thus formed are largely normal in gene expression, survive to postnatal stages, and are physiologically functional. Our results indicate that Pou4f2 and Isl1 compose a minimally sufficient regulatory core for the RGC fate. We further conclude that during development a core group of limited transcription factors, including Pou4f2 and Isl1, function downstream of Atoh7 to determine the RGC fate and initiate RGC differentiation.

Comprehensive Understanding of the Interaction Among Stress Hormones Signalling Pathways by Gene Co-expression Network

2019 ◽  
Vol 14 (7) ◽  
pp. 602-613 ◽  
Author(s):  
Maryam Mortezaeefar ◽  
Reza Fotovat ◽  
Farid Shekari ◽  
Shahryar Sasani
Keyword(s):  
Cell Cycle ◽  
Salicylic Acid ◽  
Transcription Factors ◽  
Abscisic Acid ◽  
Jasmonic Acid ◽  
Expression Patterns ◽  
Stress Hormones ◽  
Signalling Pathways ◽  
Cell Functions ◽  
The Individual

Background: Plants respond to various stresses at the same time. Recent studies show that interactions of various phytohormones can play important roles in response to stresses. Objective: Although many studies have been done about the effects of the individual hormones, little information exists about the crosstalk among the hormone signalling pathways in plants. Methods: In this work, the weighted gene co-expression network analysis method was used to define modules containing genes with highly correlated expression patterns in response to abscisic acid, jasmonic acid, and salicylic acid in Arabidopsis. Results: Results indicate that plant hormones cause major changes the expression profile and control diverse cell functions, including response to environmental stresses and external factors, cell cycle, and antioxidant activity. In addition, AtbHLH15 and HY5 transcription factors can participate in phytochrome pathways in response to the phytohormones. It is probable that some Type III WRKY transcription factors control the response to bacterium separately from the other stresses. The E2Fa/DPa transcription factor also regulates the cell cycle. Conclusion: In general, many processes and pathways in plants may be regulated using a combination of abscisic acid, jasmonic acid, and salicylic acid.

scholarly journals Headless flies generated by developmental pathway interference

Development ◽  
2001 ◽  
Vol 128 (17) ◽  
pp. 3307-3319 ◽  
Author(s):  
Renjie Jiao ◽  
Michael Daube ◽  
Hong Duan ◽  
Yu Zou ◽  
Erich Frei ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factors ◽  
Ectopic Expression ◽  
Developmental Pathway ◽  
Cone Cell ◽  
Developmental Program ◽  
Surveillance Mechanism ◽  
Antennal Disc ◽  
Development And Evolution

Ectopic expression of transcription factors in eye-antennal discs of Drosophila strongly interferes with their developmental program. Early ectopic expression in embryonic discs interferes with the developmental pathway primed by Eyeless and generates headless flies, which suggests that Eyeless is necessary for initiating cell proliferation and development of both the eye and antennal disc. Interference occurs through a block in the cell cycle that for some ectopic transcription factors is overcome by D-CycE or D-Myc. Late ectopic expression in cone cell precursors interferes with their differentiation. We propose that this developmental pathway interference is a general surveillance mechanism that eliminates most aberrations in the genetic program during development and evolution, and thus seriously restricts the pathways that evolution may take.

scholarly journals Regulation of transcription reactivation dynamics exiting mitosis

2020 ◽  
Author(s):  
Sergio Sarnataro ◽  
Andrea Riba ◽  
Nacho Molina
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Control Cell ◽  
Core Gene ◽  
Regulation Of Transcription ◽  
Gene Regulatory

AbstractProliferating cells experience a global reduction of transcription during mitosis, yet their cell identity is maintained and regulatory information is propagated from mother to daughter cells. Mitotic bookmarking by transcription factors has been proposed as a potential mechanism to ensure the reactivation of transcription at the proper set of genes exiting mitosis. Recently, mitotic transcription and waves of transcription reactivation have been observed in synchronized populations of human hepatoma cells. However, the study did not consider that mitotic-arrested cell populations progressively desynchronize leading to measurements of gene expression on a mixture of cells at different internal cell-cycle times. Moreover, it is not well understood yet what is the precise role of mitotic bookmarking on mitotic transcription as well as on the transcription reactivation waves. Ultimately, the core gene regulatory network driving the precise transcription reactivation dynamics remains to be identified. To address these questions, we developed a mathematical model to correct for the progressive desynchronization of cells and estimate gene expression dynamics with respect to a cell-cycle pseudotime. Furthermore, we used a multiple linear regression model to infer transcription factor activity dynamics. Our analysis allows us to characterize waves of transcription factor activities exiting mitosis and identify a core gene regulatory network responsible of the transcription reactivation dynamics. Moreover, we identified more than 60 transcription factors that are highly active during mitosis and represent new candidates of mitotic bookmarking factors which could represent relevant therapeutic targets to control cell proliferation.

The Role of Retinoblastoma Protein in Cell Cycle Regulation: An Updated Review

2021 ◽  
Vol 20 ◽  
Author(s):  
Rabih Roufayel ◽  
Rabih Mezher ◽  
Kenneth B. Storey
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factors ◽  
Cell Cycle Control ◽  
Expression Of Genes ◽  
E2f Transcription Factor ◽  
Cellular Energetics ◽  
Development And Differentiation ◽  
E2f Transcription Factors ◽  
Rb Phosphorylation

: Selected transcription factors have critical roles to play in organism survival by regulating the expression of genes that control the adaptations needed to handle stress conditions. The retinoblastoma (Rb) protein coupled with the E2F transcription factor family was demonstrated to have roles in controlling the cell cycle during freezing and associated environmental stresses (anoxia, dehydration). Rb phosphorylation or acetylation at different sites provide a mechanism for repressing cell proliferation that is under the control of E2F transcription factors in animals facing stresses that disrupt cellular energetics or cell volume controls. Other central regulators of the cell cycle including Cyclins, Cyclin dependent kinases (Cdks), and checkpoint proteins detect DNA damage or any improper replication, blocking further progression of cell cycle and interrupting cell proliferation. This review provides an insight into the molecular regulatory mechanisms of cell cycle control, focusing on Rb-E2F along with Cyclin-Cdk complexes typically involved in development and differentiation that need to be regulated in order to survive extreme cellular stress.

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