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 The transcription factor NKX2-2 regulates oligodendrocyte differentiation through domain-specific interactions with transcriptional corepressors

2020 ◽  
Vol 295 (7) ◽  
pp. 1879-1888
Author(s):  
Chengfu Zhang ◽  
Hao Huang ◽  
Zhen Chen ◽  
Zunyi Zhang ◽  
Wenwen Lu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Fate ◽  
Dna Methyltransferase ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Structural Domains ◽  
Histone Deacetylase 1 ◽  
Terminal Domain ◽  
Transcriptional Corepressors

The homeodomain protein NK2 homeobox 2 (NKX2-2) is a transcription factor that plays a critical role in the control of cell fate specification and differentiation in many tissues. In the developing central nervous system, this developmentally important transcription factor functions as a transcriptional repressor that governs oligodendrocyte (OL) differentiation and myelin gene expression, but the roles of various NKX2-2 structural domains in this process are unclear. In this study, using in situ hybridization, immunofluorescence, and coimmunoprecipitation, we determined the structural domains that mediate the repressive functions of murine NKX2-2 and identified the transcriptional corepressors that interact with it in OL cells. Through in ovo electroporation in embryonic chicken spinal cords, we demonstrate that the N-terminal Tinman domain and C-terminal domain synergistically promote OL differentiation by recruiting distinct transcriptional corepressors, including enhancer of split Groucho 3 (GRG3), histone deacetylase 1 (HDAC1), and DNA methyltransferase 3 α (DNMT3A). We also observed that the NK2-specific domain suppresses the function of the C-terminal domain in OL differentiation. These findings delineate the distinct NKX2-2 domains and their roles in OL differentiation and suggest that NKX2-2 regulates differentiation by repressing gene expression via multiple cofactors and molecular mechanisms.

scholarly journals Conversion of Germ Cells to Somatic Cell Types in C. elegans

2020 ◽  
Vol 8 (4) ◽  
pp. 24 ◽  
Author(s):  
Nida ul Fatima ◽  
Baris Tursun
Keyword(s):  
Transcription Factor ◽  
Germ Cell ◽  
Somatic Cell ◽  
Cell Fate ◽  
Germ Cells ◽  
Molecular Mechanisms ◽  
Essential Property ◽  
C Elegans ◽  
Differentiated Cells ◽  
A Cell

The potential of a cell to produce all types of differentiated cells in an organism is termed totipotency. Totipotency is an essential property of germ cells, which constitute the germline and pass on the parental genetic material to the progeny. The potential of germ cells to give rise to a whole organism has been the subject of intense research for decades and remains important in order to better understand the molecular mechanisms underlying totipotency. A better understanding of the principles of totipotency in germ cells could also help to generate this potential in somatic cell lineages. Strategies such as transcription factor-mediated reprogramming of differentiated cells to stem cell-like states could benefit from this knowledge. Ensuring pluripotency or even totipotency of reprogrammed stem cells are critical improvements for future regenerative medicine applications. The C. elegans germline provides a unique possibility to study molecular mechanisms that maintain totipotency and the germ cell fate with its unique property of giving rise to meiotic cells Studies that focused on these aspects led to the identification of prominent chromatin-repressing factors such as the C. elegans members of the Polycomb Repressive Complex 2 (PRC2). In this review, we summarize different factors that were recently identified, which use molecular mechanisms such as control of protein translation or chromatin repression to ensure maintenance of totipotency and the germline fate. Additionally, we focus on recently identified factors involved in preventing transcription-factor-mediated conversion of germ cells to somatic lineages. These so-called reprogramming barriers have been shown in some instances to be conserved with regard to their function as a cell fate safeguarding factor in mammals. Overall, continued studies assessing the different aspects of molecular pathways involved in maintaining the germ cell fate in C. elegans may provide more insight into cell fate safeguarding mechanisms also in other species.

scholarly journals Gene enrichment profiles reveal T-cell development, differentiation, and lineage-specific transcription factors including ZBTB25 as a novel NF-AT repressor

Blood ◽  
2010 ◽  
Vol 115 (26) ◽  
pp. 5376-5384 ◽  
Author(s):  
Yair Benita ◽  
Zhifang Cao ◽  
Cosmas Giallourakis ◽  
Chun Li ◽  
Agnès Gardet ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
T Cell Development ◽  
Gene Enrichment ◽  
Cell Tissue ◽  
Development And Differentiation ◽  
A Cell ◽  
And Function

Abstract The identification of transcriptional regulatory networks, which control tissue-specific development and function, is of central importance to the understanding of lymphocyte biology. To decipher transcriptional networks in T-cell development and differentiation we developed a browsable expression atlas and applied a novel quantitative method to define gene sets most specific to each of the represented cell subsets and tissues. Using this system, body atlas size datasets can be used to examine gene enrichment profiles from a cell/tissue perspective rather than gene perspective, thereby identifying highly enriched genes within a cell type, which are often key to cellular differentiation and function. A systems analysis of transcriptional regulators within T cells during different phases of development and differentiation resulted in the identification of known key regulators and uncharacterized coexpressed regulators. ZBTB25, a BTB-POZ family transcription factor, was identified as a highly T cell–enriched transcription factor. We provide evidence that ZBTB25 functions as a negative regulator of nuclear factor of activated T cells (NF-AT) activation, such that RNA interference mediated knockdown resulted in enhanced activation of target genes. Together, these findings suggest a novel mechanism for NF-AT mediated gene expression and the compendium of expression data provides a quantitative platform to drive exploration of gene expression across a wide range of cell/tissue types.

scholarly journals Cadherins in early neural development

2021 ◽  
Author(s):  
Karolina Punovuori ◽  
Mattias Malaguti ◽  
Sally Lowell
Keyword(s):  
Adhesion Molecules ◽  
Cell Fate ◽  
Neural Development ◽  
Ex Vivo ◽  
Directed Differentiation ◽  
Culture Dish ◽  
Cell Identity ◽  
Cell Fate Decisions ◽  
Neural Tissues ◽  
And Function

AbstractDuring early neural development, changes in signalling inform the expression of transcription factors that in turn instruct changes in cell identity. At the same time, switches in adhesion molecule expression result in cellular rearrangements that define the morphology of the emerging neural tube. It is becoming increasingly clear that these two processes influence each other; adhesion molecules do not simply operate downstream of or in parallel with changes in cell identity but rather actively feed into cell fate decisions. Why are differentiation and adhesion so tightly linked? It is now over 60 years since Conrad Waddington noted the remarkable "Constancy of the Wild Type” (Waddington in Nature 183: 1654–1655, 1959) yet we still do not fully understand the mechanisms that make development so reproducible. Conversely, we do not understand why directed differentiation of cells in a dish is sometimes unpredictable and difficult to control. It has long been suggested that cells make decisions as 'local cooperatives' rather than as individuals (Gurdon in Nature 336: 772–774, 1988; Lander in Cell 144: 955–969, 2011). Given that the cadherin family of adhesion molecules can simultaneously influence morphogenesis and signalling, it is tempting to speculate that they may help coordinate cell fate decisions between neighbouring cells in the embryo to ensure fidelity of patterning, and that the uncoupling of these processes in a culture dish might underlie some of the problems with controlling cell fate decisions ex-vivo. Here we review the expression and function of cadherins during early neural development and discuss how and why they might modulate signalling and differentiation as neural tissues are formed.

scholarly journals HOS15 is a transcriptional corepressor of NPR1-mediated gene activation of plant immunity

2020 ◽  
Vol 117 (48) ◽  
pp. 30805-30815
Author(s):  
Mingzhe Shen ◽  
Chae Jin Lim ◽  
Junghoon Park ◽  
Jeong Eun Kim ◽  
Dongwon Baek ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ubiquitin Ligase ◽  
Transcriptional Activation ◽  
Plant Immunity ◽  
Gene Activation ◽  
Transcriptional Corepressor ◽  
Defense Gene Expression ◽  
Dynamic Regulation ◽  
Defense Gene ◽  
Transcriptional Corepressors

Transcriptional regulation is a complex and pivotal process in living cells. HOS15 is a transcriptional corepressor. Although transcriptional repressors generally have been associated with inactive genes, increasing evidence indicates that, through poorly understood mechanisms, transcriptional corepressors also associate with actively transcribed genes. Here, we show that HOS15 is the substrate receptor for an SCF/CUL1 E3 ubiquitin ligase complex (SCFHOS15) that negatively regulates plant immunity by destabilizing transcriptional activation complexes containing NPR1 and associated transcriptional activators. In unchallenged conditions, HOS15 continuously eliminates NPR1 to prevent inappropriate defense gene expression. Upon defense activation, HOS15 preferentially associates with phosphorylated NPR1 to stimulate rapid degradation of transcriptionally active NPR1 and thus limit the extent of defense gene expression. Our findings indicate that HOS15-mediated ubiquitination and elimination of NPR1 produce effects contrary to those of CUL3-containing ubiquitin ligase that coactivate defense gene expression. Thus, HOS15 plays a key role in the dynamic regulation of pre- and postactivation host defense.

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 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 A single cell brain atlas in human Alzheimer’s disease

2019 ◽  
Author(s):  
Alexandra Grubman ◽  
Gabriel Chew ◽  
John F. Ouyang ◽  
Guizhi Sun ◽  
Xin Yi Choo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Single Cell ◽  
Cell Fate ◽  
Expression Patterns ◽  
Cell Types ◽  
Gene Expression Patterns ◽  
Cell Type ◽  
Web Resource ◽  
Cell Type Specific

AbstractAlzheimer’s disease (AD) is a heterogeneous disease that is largely dependent on the complex cellular microenvironment in the brain. This complexity impedes our understanding of how individual cell types contribute to disease progression and outcome. To characterize the molecular and functional cell diversity in the human AD brain we utilized single nuclei RNA- seq in AD and control patient brains in order to map the landscape of cellular heterogeneity in AD. We detail gene expression changes at the level of cells and cell subclusters, highlighting specific cellular contributions to global gene expression patterns between control and Alzheimer’s patient brains. We observed distinct cellular regulation of APOE which was repressed in oligodendrocyte progenitor cells (OPCs) and astrocyte AD subclusters, and highly enriched in a microglial AD subcluster. In addition, oligodendrocyte and microglia AD subclusters show discordant expression of APOE. Integration of transcription factor regulatory modules with downstream GWAS gene targets revealed subcluster-specific control of AD cell fate transitions. For example, this analysis uncovered that astrocyte diversity in AD was under the control of transcription factor EB (TFEB), a master regulator of lysosomal function and which initiated a regulatory cascade containing multiple AD GWAS genes. These results establish functional links between specific cellular sub-populations in AD, and provide new insights into the coordinated control of AD GWAS genes and their cell-type specific contribution to disease susceptibility. Finally, we created an interactive reference web resource which will facilitate brain and AD researchers to explore the molecular architecture of subtype and AD-specific cell identity, molecular and functional diversity at the single cell level.HighlightsWe generated the first human single cell transcriptome in AD patient brainsOur study unveiled 9 clusters of cell-type specific and common gene expression patterns between control and AD brains, including clusters of genes that present properties of different cell types (i.e. astrocytes and oligodendrocytes)Our analyses also uncovered functionally specialized sub-cellular clusters: 5 microglial clusters, 8 astrocyte clusters, 6 neuronal clusters, 6 oligodendrocyte clusters, 4 OPC and 2 endothelial clusters, each enriched for specific ontological gene categoriesOur analyses found manifold AD GWAS genes specifically associated with one cell-type, and sets of AD GWAS genes co-ordinately and differentially regulated between different brain cell-types in AD sub-cellular clustersWe mapped the regulatory landscape driving transcriptional changes in AD brain, and identified transcription factor networks which we predict to control cell fate transitions between control and AD sub-cellular clustersFinally, we provide an interactive web-resource that allows the user to further visualise and interrogate our dataset.Data resource web interface:http://adsn.ddnetbio.com

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 Defining cell identity beyond the premise of differential gene expression

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Hani Jieun Kim ◽  
Patrick P. L. Tam ◽  
Pengyi Yang
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Cell Fate ◽  
Differential Gene Expression ◽  
Cell Types ◽  
Cell Identity ◽  
Gene Transcripts ◽  
Differential Gene ◽  
Biological Attributes

AbstractIdentifying genes that define cell identity is a requisite step for characterising cell types and cell states and predicting cell fate choices. By far, the most widely used approach for this task is based on differential expression (DE) of genes, whereby the shift of mean expression are used as the primary statistics for identifying gene transcripts that are specific to cell types and states. While DE-based methods are useful for pinpointing genes that discriminate cell types, their reliance on measuring difference in mean expression may not reflect the biological attributes of cell identity genes. Here, we highlight the quest for non-DE methods and provide an overview of these methods and their applications to identify genes that define cell identity and functionality.

Sign in / Sign up

Export Citation Format

Share Document