scholarly journals Epigenetic inactivation of oncogenic brachyury (TBXT) by H3K27 histone demethylase controls chordoma cell survival

2018 ◽  
Author(s):  
Lucia Cottone ◽  
Edward S Hookway ◽  
Adam Cribbs ◽  
Graham Wells ◽  
Patrick Lombard ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Control Mechanisms ◽  
Rare Tumour ◽  
Mesoderm Development ◽  
Survival Pathways ◽  
Genome Wide ◽  
Notochord Cell ◽  
Oncogenic Driver ◽  
And Function

AbstractThe expression of the transcription factorbrachyury(TBXT) is normally restricted to embryonic development and its silencing after mesoderm development is epigenetically regulated. In chordoma, a rare tumour of notochordal differentiation, TBXT acts as a putative oncogene, and we hypothesised that its expression could be controlled through epigenetic inhibition. Screening of five chordoma cell lines revealed that only inhibitors of the histone 3 lysine 27 demethylases KDM6A (UTX) and KDM6B (Jmjd3) reduceTBXTexpression and lead to cell death, findings validated in primary patient-derived culture systems. Pharmacological inhibition of KDM6 demethylases leads to genome-wide increases in repressive H3K27me3 marks, accompanied by significantly reduced TBXT expression, an effect that is phenocopied by the dual genetic inactivation ofKDM6A/Busing CRISPR/Cas9. Transcriptional profiles in response to a novel KDM6A/B inhibitor, KDOBA67, revealed downregulation of critical genes and transcription factor networks for chordoma survival pathways, whereas upregulated pathways were dominated by stress, cell cycle and pro-apoptotic response pathways.This study supports previous data showing that the function of TBXT is essential for maintaining notochord cell fate and function and provides further evidence that TBXT is an oncogenic driver in chordoma. Moreover, the data suggest that TBXT can potentially be targeted therapeutically by modulating epigenetic control mechanisms such as H3K27 demethylases.

scholarly journals BATF acts as an essential regulator of IL-25–responsive migratory ILC2 cell fate and function

2020 ◽  
Vol 5 (43) ◽  
pp. eaay3994 ◽  
Author(s):  
Mindy M. Miller ◽  
Preeyam S. Patel ◽  
Katherine Bao ◽  
Thomas Danhorn ◽  
Brian P. O’Connor ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Leucine Zipper ◽  
Mucosal Barrier ◽  
Nippostrongylus Brasiliensis ◽  
Cell Hyperplasia ◽  
Basic Leucine Zipper ◽  
Tuft Cell ◽  
Group 2 ◽  
And Function

A transitory, interleukin-25 (IL-25)–responsive, group 2 innate lymphoid cell (ILC2) subset induced during type 2 inflammation was recently identified as iILC2s. This study focuses on understanding the significance of this population in relation to tissue-resident nILC2s in the lung and intestine. RNA-sequencing and pathway analysis revealed the AP-1 superfamily transcription factor BATF (basic leucine zipper transcription factor, activating transcription factor–like) as a potential modulator of ILC2 cell fate. Infection of BATF-deficient mice with Nippostrongylus brasiliensis showed a selective defect in IL-25–mediated helminth clearance and a corresponding loss of iILC2s in the lung characterized as IL-17RBhigh, KLRG1high, BATFhigh, and Arg1low. BATF deficiency selectively impaired iILC2s because it had no impact on tissue-resident nILC2 frequency or function. Pulmonary-associated iILC2s migrated to the lung after infection, where they represented an early source of IL-4 and IL-13. Although the composition of ILC2s in the small intestine was distinct from those in the lung, their frequency and IL-13 expression remained dependent on BATF, which was also required for optimal goblet and tuft cell hyperplasia. Findings support IL-25–responsive ILC2s as early sentinels of mucosal barrier integrity.

scholarly journals Putative oncogene Brachyury (T) is essential to specify cell fate but dispensable for notochord progenitor proliferation and EMT

2016 ◽  
Vol 113 (14) ◽  
pp. 3820-3825 ◽  
Author(s):  
Jianjian Zhu ◽  
Kin Ming Kwan ◽  
Susan Mackem
Keyword(s):  
Cell Fate ◽  
Epithelial Mesenchymal Transition ◽  
Primitive Streak ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Mesenchymal Transition ◽  
Neural Fate ◽  
Notochord Cell ◽  
Genetic Lineage Tracing ◽  
And Function

The transcription factor Brachyury (T) gene is expressed throughout primary mesoderm (primitive streak and notochord) during early embryonic development and has been strongly implicated in the genesis of chordoma, a sarcoma of notochord cell origin. Additionally, T expression has been found in and proposed to play a role in promoting epithelial–mesenchymal transition (EMT) in various other types of human tumors. However, the role of T in normal mammalian notochord development and function is still not well-understood. We have generated an inducible knockdown model to efficiently and selectively deplete T from notochord in mouse embryos. In combination with genetic lineage tracing, we show that T function is essential for maintaining notochord cell fate and function. Progenitors adopt predominantly a neural fate in the absence of T, consistent with an origin from a common chordoneural progenitor. However, T function is dispensable for progenitor cell survival, proliferation, and EMT, which has implications for the therapeutic targeting of T in chordoma and other cancers.

scholarly journals In vivo single cell analysis reveals Gata2 dynamics in cells transitioning to hematopoietic fate

2017 ◽  
Vol 215 (1) ◽  
pp. 233-248 ◽  
Author(s):  
Christina Eich ◽  
Jochen Arlt ◽  
Chris S. Vink ◽  
Parham Solaimani Kartalaei ◽  
Polynikis Kaimakis ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Regulatory Networks ◽  
Single Cell Analysis ◽  
Single Cells ◽  
Time Lapse ◽  
Hematopoietic Stem ◽  
And Function ◽  
In Cells

Cell fate is established through coordinated gene expression programs in individual cells. Regulatory networks that include the Gata2 transcription factor play central roles in hematopoietic fate establishment. Although Gata2 is essential to the embryonic development and function of hematopoietic stem cells that form the adult hierarchy, little is known about the in vivo expression dynamics of Gata2 in single cells. Here, we examine Gata2 expression in single aortic cells as they establish hematopoietic fate in Gata2Venus mouse embryos. Time-lapse imaging reveals rapid pulsatile level changes in Gata2 reporter expression in cells undergoing endothelial-to-hematopoietic transition. Moreover, Gata2 reporter pulsatile expression is dramatically altered in Gata2+/− aortic cells, which undergo fewer transitions and are reduced in hematopoietic potential. Our novel finding of dynamic pulsatile expression of Gata2 suggests a highly unstable genetic state in single cells concomitant with their transition to hematopoietic fate. This reinforces the notion that threshold levels of Gata2 influence fate establishment and has implications for transcription factor–related hematologic dysfunctions.

scholarly journals Fate Before Function: Specification of the Hair Follicle Niche Occurs Prior to its Formation and Is Progenitor Dependent

2018 ◽  
Author(s):  
Ka-Wai Mok ◽  
Nivedita Saxena ◽  
Nicholas Heitman ◽  
Laura Grisanti ◽  
Devika Srivastava ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Single Cell ◽  
Hair Follicle ◽  
Cell Fate ◽  
Cluster Formation ◽  
Developmental Trajectory ◽  
List Type ◽  
Molecular Events ◽  
Niche Formation ◽  
And Function

SUMMARYCell fate transitions are essential for specialization of stem cells and their niches, but the precise timing and sequence of molecular events during embryonic development are largely unknown. Here, we show that dermal condensates (DC), signaling niches for epithelial progenitors in hair placodes, are specified before niche formation and function. With 3D/4D microscopy we identify unclustered DC precursors. With population-based and single-cell transcriptomics we define a molecular time-lapse of dynamic niche signatures and the developmental trajectory as the DC lineage emerges from fibroblasts. Co-expression of downregulated fibroblast and upregulated DC genes in niche precursors reveals a transitory molecular state following a proliferation shutdown. Waves of transcription factor and signaling molecule expression then consolidate DC niche formation. Finally, ablation of epidermal Wnt signaling and placode-derived FGF20 demonstrates their requirement for DC-precursor specification. These findings uncover a progenitor-dependent niche precursor fate and the transitory molecular events controlling niche formation and function.Graphical AbstractHIGHLIGHTSPrecursors of the hair follicle niche are specified before niche cluster formationBulk/single cell RNA-seq defines early niche fate at molecular transitional stateSuccessive waves of transcription factor/signaling genes mark niche fate acquisitionNiche fate acquisition is not “pre-programmed” and requires FGF20 from progenitors

scholarly journals The transcriptional corepressor CTBP-1 acts with the SOX family transcription factor EGL-13 to maintain AIA interneuron cell identity in C. elegans

2021 ◽  
Author(s):  
Josh Saul ◽  
Takashi Hirose ◽  
Robert Horvitz
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Fate ◽  
Transcriptional Corepressor ◽  
Cell Identity ◽  
C Elegans ◽  
Dna Binding Specificity ◽  
A Cell ◽  
Transcriptional Corepressors ◽  
And Function

Cell identity is characterized by a distinct combination of gene expression, cell morphology and cellular function established as progenitor cells divide and differentiate. Following establishment, cell identities can be unstable and require active and continuous maintenance throughout the remaining life of a cell. Mechanisms underlying the maintenance of cell identities are incompletely understood. Here we show that the gene ctbp-1, which encodes the transcriptional corepressor C-terminal binding protein-1 (CTBP-1), is essential for the maintenance of the identities of the two AIA interneurons in the nematode Caenorhabditis elegans. ctbp-1 is not required for the establishment of the AIA cell fate but rather functions cell-autonomously and can act in older worms to maintain proper AIA gene expression, morphology and function. From a screen for suppressors of the ctbp-1 mutant phenotype, we identified the gene egl-13, which encodes a SOX family transcription factor. We found that egl-13 regulates AIA function and aspects of AIA gene expression, but not AIA morphology. We conclude that the CTBP-1 protein maintains AIA cell identity in part by utilizing EGL-13 to repress transcriptional activity in the AIAs. More generally, we propose that transcriptional corepressors like CTBP-1 might be critical factors in the maintenance of cell identities, harnessing the DNA-binding specificity of transcription factors like EGL-13 to selectively regulate gene expression in a cell-specific manner.

scholarly journals Genome-wide identification of long non-coding RNA targets of the tomato MADS box transcription factor RIN and function analysis

2018 ◽  
Vol 123 (3) ◽  
pp. 469-482 ◽  
Author(s):  
Tongtong Yu ◽  
David T W Tzeng ◽  
Ran Li ◽  
Jianye Chen ◽  
Silin Zhong ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Function Analysis ◽  
Mads Box ◽  
Non Coding Rna ◽  
Rna Targets ◽  
Genome Wide ◽  
And Function ◽  
Long Non Coding Rna

scholarly journals Transcription Factor Bcl11b Controls Effector and Memory CD8 T cell Fate Decision and Function during Poxvirus Infection

2016 ◽  
Vol 7 ◽  
Author(s):  
Georges Abboud ◽  
Jessica Stanfield ◽  
Vikas Tahiliani ◽  
Pritesh Desai ◽  
Tarun E. Hutchinson ◽  
...  
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Cell Fate ◽  
Cd8 T Cell ◽  
Cell Fate Decision ◽  
Memory Cd8 T Cell ◽  
Fate Decision ◽  
And Function

scholarly journals Specification of diverse cell types during early neurogenesis of the mouse cerebellum

2018 ◽  
Author(s):  
John W. Wizeman ◽  
Qiuxia Guo ◽  
Elliot Wilion ◽  
James Y.H. Li
Keyword(s):  
Cell Fate ◽  
Developmental Trajectories ◽  
Ventricular Zone ◽  
Cell Types ◽  
Genome Wide ◽  
Integral Role ◽  
Cerebellar Cell ◽  
Early Neurogenesis ◽  
And Function ◽  
Developing Cerebellum

SUMMARYWe applied single-cell RNA sequencing to profile genome-wide gene expression in about 9,400 individual cerebellar cells from the mouse embryo at embryonic day 13.5. Reiterative clustering identified the major cerebellar cell types and subpopulations of different lineages. Through pseudotemporal ordering to reconstruct developmental trajectories, we identified novel transcriptional programs controlling cell fate specification of populations arising from the ventricular zone and the anterior rhombic lip, two distinct germinal zones of the embryonic cerebellum. Together, our data revealed cell-specific markers for studying the cerebellum, important specification decisions, and a number of previously unknown subpopulations that may play an integral role in the formation and function of the cerebellum. Importantly, we identified a potential mechanism of vermis formation, which is affected by multiple congenital cerebellar defects. Our findings will facilitate new discovery by providing insights into the molecular and cell type diversity in the developing cerebellum.

Genome-Wide Transcript Profiling Reveals an Auxin-Responsive Transcription Factor, OsAP2/ERF-40, Promoting Rice Adventitious Root Development

2019 ◽  
Vol 60 (10) ◽  
pp. 2343-2355 ◽  
Author(s):  
Ananya Neogy ◽  
Tushar Garg ◽  
Anil Kumar ◽  
Anuj K Dwivedi ◽  
Harshita Singh ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Signaling Pathways ◽  
Cell Fate ◽  
Transcriptional Activation ◽  
Adventitious Root ◽  
Grass Species ◽  
Ethylene Response Factor ◽  
Hormone Signaling ◽  
Developmental Program ◽  
Genome Wide

Abstract Unlike dicots, the robust root system in grass species largely originates from stem base during postembryonic development. The mechanisms by which plant hormone signaling pathways control the architecture of adventitious root remain largely unknown. Here, we studied the modulations in global genes activity in developing rice adventitious root by genome-wide RNA sequencing in response to external auxin and cytokinin signaling cues. We further analyzed spatiotemporal regulations of key developmental regulators emerged from our global transcriptome analysis. Interestingly, some of the key cell fate determinants such as homeodomain transcription factor (TF), OsHOX12, no apical meristem protein, OsNAC39, APETALA2/ethylene response factor, OsAP2/ERF-40 and WUSCHEL-related homeobox, OsWOX6.1 and OsWOX6.2, specifically expressed in adventitious root primordia. Functional analysis of one of these regulators, an auxin-induced TF containing AP2/ERF domain, OsAP2/ERF-40, demonstrates its sufficiency to confer the adventitious root fate. The ability to trigger the root developmental program is largely attributed to OsAP2/ERF-40-mediated dose-dependent transcriptional activation of genes that can facilitate generating effective auxin response, and OsERF3–OsWOX11–OsRR2 pathway. Our studies reveal gene regulatory network operating in response to hormone signaling pathways and identify a novel TF regulating adventitious root developmental program, a key agronomically important quantitative trait, upstream of OsERF3–OsWOX11–OsRR2 pathway.

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