scholarly journals Adaptive methylation regulation of p53 pathway in sympatric speciation of blind mole rats, Spalax

2016 ◽  
Vol 113 (8) ◽  
pp. 2146-2151 ◽  
Author(s):  
Yang Zhao ◽  
Jia-Wei Tang ◽  
Zhi Yang ◽  
Yi-Bin Cao ◽  
Ji-Long Ren ◽  
...  
Keyword(s):  
Cell Fate ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Expression Patterns ◽  
Sympatric Speciation ◽  
Activator Protein 1 ◽  
Sympatric Populations ◽  
Cycle Arrest ◽  
Mole Rat ◽  
Site Mutagenesis

Epigenetic modifications play significant roles in adaptive evolution. The tumor suppressor p53, well known for controlling cell fate and maintaining genomic stability, is much less known as a master gene in environmental adaptation involving methylation modifications. The blind subterranean mole rat Spalax eherenbergi superspecies in Israel consists of four species that speciated peripatrically. Remarkably, the northern Galilee species Spalax galili (2n = 52) underwent adaptive ecological sympatric speciation, caused by the sharply divergent chalk and basalt ecologies. This was demonstrated by mitochondrial and nuclear genomic evidence. Here we show that the expression patterns of the p53 regulatory pathway diversified between the abutting sympatric populations of S. galili in sharply divergent chalk–basalt ecologies. We identified higher methylation on several sites of the p53 promoter in the population living in chalk soil (chalk population). Site mutagenesis showed that methylation on these sites linked to the transcriptional repression of p53 involving Cut-Like Homeobox 1 (Cux1), paired box 4 (Pax 4), Pax 6, and activator protein 1 (AP-1). Diverse expression levels of p53 between the incipiently sympatrically speciating chalk–basalt abutting populations of S. galili selectively affected cell-cycle arrest but not apoptosis. We hypothesize that methylation modification of p53 has adaptively shifted in supervising its target genes during sympatric speciation of S. galili to cope with the contrasting environmental stresses of the abutting divergent chalk–basalt ecologies.

scholarly journals Differential regulation of gastrulation and neuroectodermal gene expression by Snail in the Drosophila embryo

Development ◽  
1997 ◽  
Vol 124 (19) ◽  
pp. 3683-3691 ◽  
Author(s):  
K. Hemavathy ◽  
X. Meng ◽  
Y.T. Ip
Keyword(s):  
Cell Fate ◽  
Target Genes ◽  
Expression Patterns ◽  
Cell Movement ◽  
Drosophila Embryo ◽  
Intermediate Phenotype ◽  
Gene Products ◽  
Mesodermal Cell ◽  
Possible Cause ◽  
Mesodermal Lineage

The initiation of mesoderm differentiation in the Drosophila embryo requires the gene products of twist and snail. In either mutant, the ventral cell invagination during gastrulation is blocked and no mesoderm-derived tissue is formed. One of the functions of Snail is to repress neuroectodermal genes and restrict their expressions to the lateral regions. The derepression of the neuroectodermal genes into the ventral region in snail mutant is a possible cause of defects in gastrulation and in mesoderm differentiation. To investigate such possibility, we analysed a series of snail mutant alleles. We found that different neuroectodermal genes respond differently in various snail mutant background. Due to the differential response of target genes, one of the mutant alleles, V2, that has reduced Snail function showed an intermediate phenotype. In V2 embryos, neuroectodermal genes, such as single-minded and rhomboid, are derepressed while ventral invagination proceeds normally. However, the differentiation of these invaginated cells into mesodermal lineage is disrupted. The results suggest that the establishment of mesodermal cell fate requires the proper restriction of neuroectodermal genes, while the ventral cell movement is independent of the expression patterns of these genes. Together with the data showing that the expression of some ventral genes disappear in snail mutants, we propose that Snail may repress or activate another set of target genes that are required specifically for gastrulation.

Identifying targets of the rough homeobox gene of Drosophila: evidence that rhomboid functions in eye development

Development ◽  
1992 ◽  
Vol 116 (2) ◽  
pp. 335-346 ◽  
Author(s):  
M. Freeman ◽  
B.E. Kimmel ◽  
G.M. Rubin
Keyword(s):  
Cell Fate ◽  
Target Genes ◽  
Eye Development ◽  
Expression Patterns ◽  
Ectopic Expression ◽  
Homeobox Gene ◽  
Homeodomain Protein ◽  
Dorsoventral Patterning ◽  
Altered Expression ◽  
Enhancer Trap Lines

In order to identify potential target genes of the rough homeodomain protein, which is known to specify some aspects of the R2/R5 photoreceptor subtype in the Drosophila eye, we have carried out a search for enhancer trap lines whose expression is rough-dependent. We crossed 101 enhancer traps that are expressed in the developing eye into a rough mutant background, and have identified seven lines that have altered expression patterns. One of these putative rough target genes is rhomboid, a gene known to be required for dorsoventral patterning and development of some of the nervous system in the embryo. We have examined the role of rhomboid in eye development and find that, while mutant clones have only a subtle phenotype, ectopic expression of the gene causes the non-neuronal mystery cells to be transformed into photoreceptors. We propose that rhomboid is a part of a partially redundant network of genes that specify photoreceptor cell fate.

scholarly journals Maximal STAT5-Induced Proliferation and Self-Renewal at Intermediate STAT5 Activity Levels

2008 ◽  
Vol 28 (21) ◽  
pp. 6668-6680 ◽  
Author(s):  
Albertus T. J. Wierenga ◽  
Edo Vellenga ◽  
Jan Jacob Schuringa
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Target Genes ◽  
Expression Patterns ◽  
Activity Levels ◽  
Dependent Manner ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions

ABSTRACT The level of transcription factor activity critically regulates cell fate decisions, such as hematopoietic stem cell (HSC) self-renewal and differentiation. We introduced STAT5A transcriptional activity into human HSCs/progenitor cells in a dose-dependent manner by overexpression of a tamoxifen-inducible STAT5A(1*6)-estrogen receptor fusion protein. Induction of STAT5A activity in CD34+ cells resulted in impaired myelopoiesis and induction of erythropoiesis, which was most pronounced at the highest STAT5A transactivation levels. In contrast, intermediate STAT5A activity levels resulted in the most pronounced proliferative advantage of CD34+ cells. This coincided with increased cobblestone area-forming cell and long-term-culture-initiating cell frequencies, which were predominantly elevated at intermediate STAT5A activity levels but not at high STAT5A levels. Self-renewal of progenitors was addressed by serial replating of CFU, and only progenitors containing intermediate STAT5A activity levels contained self-renewal capacity. By extensive gene expression profiling we could identify gene expression patterns of STAT5 target genes that predominantly associated with a self-renewal and long-term expansion phenotype versus those that identified a predominant differentiation phenotype.

scholarly journals FLIP(L) determines p53 induced life or death

2019 ◽  
Author(s):  
Andrea Lees ◽  
Alexander J. McIntyre ◽  
Fiammetta Falcone ◽  
Nyree T. Crawford ◽  
Christopher McCann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Fate ◽  
Target Genes ◽  
Hdac Inhibitors ◽  
Caspase 8 ◽  
Cycle Arrest ◽  
P53 Activation ◽  
P53 Target Genes ◽  
Mdm2 Inhibitor

AbstractHow p53 differentially activates cell cycle arrest versus cell death remains poorly understood. Here, we demonstrate that upregulation of canonical pro-apoptotic p53 target genes in colon cancer cells imposes a critical dependence on the long splice form of the caspase-8 regulator FLIP (FLIP(L)), which we identify as a direct p53 transcriptional target. Inhibiting FLIP(L) expression with siRNA or Class-I HDAC inhibitors promotes apoptosis in response to p53 activation by the MDM2 inhibitor Nutlin-3A, which otherwise predominantly induces cell-cycle arrest. When FLIP(L) upregulation is inhibited, apoptosis is induced in response to p53 activation via a novel ligand-independent TRAIL-R2/caspase-8 complex, which, by activating BID, induces mitochondrial-mediated apoptosis. Notably, FLIP(L) depletion inhibits p53-induced expression of the cell cycle regulator p21 and enhances p53-mediated upregulation of PUMA, with the latter activating mitochondrial-mediated apoptosis in FLIP(L)-depleted, Nutlin-3A-treated cells lacking TRAIL-R2/caspase-8. Thus, we report two previously undescribed, novel FLIP(L)-dependent mechanisms that determine cell fate following p53 activation.

scholarly journals Cell Fate Determination Factor DACH1 Inhibits c-Jun–induced Contact-independent Growth

2007 ◽  
Vol 18 (3) ◽  
pp. 755-767 ◽  
Author(s):  
Kongming Wu ◽  
Manran Liu ◽  
Anping Li ◽  
Howard Donninger ◽  
Mahadev Rao ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Cell Fate ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Cell Fate Determination ◽  
Fate Determination ◽  
Multiple Context ◽  
Mediated Contact ◽  
Inhibition Of Dna Synthesis

The cell fate determination factor DACH1 plays a key role in cellular differentiation in metazoans. DACH1 is engaged in multiple context-dependent complexes that activate or repress transcription. DACH1 can be recruited to DNA via the Six1/Eya bipartite transcription (DNA binding/coactivator) complex. c-Jun is a critical component of the activator protein (AP)-1 transcription factor complex and can promote contact-independent growth. Herein, DACH1 inhibited c-Jun–induced DNA synthesis and cellular proliferation. Excision of c-Jun with Cre recombinase, in c-junf1/f1 3T3 cells, abrogated DACH1-mediated inhibition of DNA synthesis. c-Jun expression rescued DACH1-mediated inhibition of cellular proliferation. DACH1 inhibited induction of c-Jun by physiological stimuli and repressed c-jun target genes (cyclin A, β-PAK, and stathmin). DACH1 bound c-Jun and inhibited AP-1 transcriptional activity. c-jun and c-fos were transcriptionally repressed by DACH1, requiring the conserved N-terminal (dac and ski/sno [DS]) domain. c-fos transcriptional repression by DACH1 requires the SRF site of the c-fos promoter. DACH1 inhibited c-Jun transactivation through the δ domain of c-Jun. DACH1 coprecipitated the histone deacetylase proteins (HDAC1, HDAC2, and NCoR), providing a mechanism by which DACH1 represses c-Jun activity through the conserved δ domain. An oncogenic v-Jun deleted of the δ domain was resistant to DACH1 repression. Collectively, these studies demonstrate a novel mechanism by which DACH1 blocks c-Jun-mediated contact-independent growth through repressing the c-Jun δ domain.

scholarly journals Distinct mechanisms control genome recognition by p53 at its target genes linked to different cell fates

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marina Farkas ◽  
Hideharu Hashimoto ◽  
Yingtao Bi ◽  
Ramana V. Davuluri ◽  
Lois Resnick-Silverman ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Binding ◽  
Cell Cycle Arrest ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Binding Modes ◽  
Cell Fate Decisions ◽  
Cycle Arrest

AbstractThe tumor suppressor p53 integrates stress response pathways by selectively engaging one of several potential transcriptomes, thereby triggering cell fate decisions (e.g., cell cycle arrest, apoptosis). Foundational to this process is the binding of tetrameric p53 to 20-bp response elements (REs) in the genome (RRRCWWGYYYN0-13RRRCWWGYYY). In general, REs at cell cycle arrest targets (e.g. p21) are of higher affinity than those at apoptosis targets (e.g., BAX). However, the RE sequence code underlying selectivity remains undeciphered. Here, we identify molecular mechanisms mediating p53 binding to high- and low-affinity REs by showing that key determinants of the code are embedded in the DNA shape. We further demonstrate that differences in minor/major groove widths, encoded by G/C or A/T bp content at positions 3, 8, 13, and 18 in the RE, determine distinct p53 DNA-binding modes by inducing different Arg248 and Lys120 conformations and interactions. The predictive capacity of this code was confirmed in vivo using genome editing at the BAX RE to interconvert the DNA-binding modes, transcription pattern, and cell fate outcome.

scholarly journals The pseudo-caspase FLIP(L) regulates cell fate following p53 activation

2020 ◽  
Vol 117 (30) ◽  
pp. 17808-17819 ◽  
Author(s):  
Andrea Lees ◽  
Alexander J. McIntyre ◽  
Nyree T. Crawford ◽  
Fiammetta Falcone ◽  
Christopher McCann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Fate ◽  
Target Genes ◽  
Caspase 8 ◽  
Cycle Arrest ◽  
P53 Activation ◽  
Induced Apoptosis

p53 is the most frequently mutated, well-studied tumor-suppressor gene, yet the molecular basis of the switch from p53-induced cell-cycle arrest to apoptosis remains poorly understood. Using a combination of transcriptomics and functional genomics, we unexpectedly identified a nodal role for the caspase-8 paralog and only human pseudo-caspase, FLIP(L), in regulating this switch. Moreover, we identify FLIP(L) as a direct p53 transcriptional target gene that is rapidly up-regulated in response to Nutlin-3A, an MDM2 inhibitor that potently activates p53. Genetically or pharmacologically inhibiting expression of FLIP(L) using siRNA or entinostat (a clinically relevant class-I HDAC inhibitor) efficiently promoted apoptosis in colorectal cancer cells in response to Nutlin-3A, which otherwise predominantly induced cell-cycle arrest. Enhanced apoptosis was also observed when entinostat was combined with clinically relevant, p53-activating chemotherapy in vitro, and this translated into enhanced in vivo efficacy. Mechanistically, FLIP(L) inhibited p53-induced apoptosis by blocking activation of caspase-8 by the TRAIL-R2/DR5 death receptor; notably, this activation was not dependent on receptor engagement by its ligand, TRAIL. In the absence of caspase-8, another of its paralogs, caspase-10 (also transcriptionally up-regulated by p53), induced apoptosis in Nutlin-3A-treated, FLIP(L)-depleted cells, albeit to a lesser extent than in caspase-8-proficient cells. FLIP(L) depletion also modulated transcription of canonical p53 target genes, suppressing p53-induced expression of the cell-cycle regulator p21 and enhancing p53-induced up-regulation of proapoptotic PUMA. Thus, even in the absence of caspase-8/10, FLIP(L) silencing promoted p53-induced apoptosis by enhancing PUMA expression. Thus, we report unexpected, therapeutically relevant roles for FLIP(L) in determining cell fate following p53 activation.

scholarly journals Pits and CtBP control tissue growth in Drosophila melanogaster with the Hippo pathway transcription repressor, Tgi

2019 ◽  
Author(s):  
Joseph H.A. Vissers ◽  
Lucas G. Dent ◽  
Colin House ◽  
Shu Kondo ◽  
Kieran F. Harvey
Keyword(s):  
Cell Fate ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Affinity Purification ◽  
Hippo Pathway ◽  
Transcriptional Response ◽  
Size Control ◽  
Tissue Growth ◽  
Organ Size ◽  
The Hippo Pathway

ABSTRACTThe Hippo pathway is an evolutionary conserved signalling network that regulates organ size, cell fate control and tumorigenesis. In the context of organ size control, the pathway incorporates a large variety of cellular cues such as cell polarity and adhesion into an integrated transcriptional response. The central Hippo signalling effector is the transcriptional co-activator Yorkie, which controls gene expression in partnership with different transcription factors, most notably Scalloped. When it is not activated by Yorkie, Scalloped can act as a repressor of transcription, at least in part due to its interaction with the corepressor protein Tgi. The mechanism by which Tgi represses transcription is incompletely understood and therefore we sought to identify proteins that potentially operate together with it. Using an affinity purification and mass-spectrometry approach we identified Pits and CtBP as Tgi-interacting proteins, both of which have been linked to transcriptional repression. Both Pits and CtBP were required for Tgi to suppress the growth of the D. melanogaster eye and CtBP loss suppressed the undergrowth of yorkie mutant eye tissue. Furthermore, as reported previously for Tgi, overexpression of Pits suppressed transcription of Hippo pathway target genes. These findings suggest that Tgi might operate together with Pits and CtBP to repress transcription of genes that normally promote tissue growth. The human orthologues of Tgi, CtBP and Pits (VGLL4, CTBP2 and IRF2BP2) physically and functionally interact to control transcription, implying that the mechanism by which these proteins control transcriptional repression is conserved throughout evolution.

The FOS/AP-1 regulates metabolic changes and cholesterol synthesis in human periovulatory granulosa cells

Endocrinology ◽  
2021 ◽  
Author(s):  
Yohan Choi ◽  
Hayce Jeon ◽  
James W Akin ◽  
Thomas E Curry Jr. ◽  
Misung Jo
Keyword(s):  
Target Genes ◽  
Cholesterol Biosynthesis ◽  
Expression Patterns ◽  
Metabolic Changes ◽  
Matrix Remodeling ◽  
Activator Protein 1 ◽  
Sequencing Data ◽  
Downstream Target ◽  
Metabolic Activities ◽  
Periovulatory Follicles

Abstract FOS, a subunit of the activator protein-1 (AP-1) transcription factor, has been implicated in various cellular changes. In the human ovary, the expression of FOS and its heterodimeric binding partners JUN, JUNB, and JUND increases in periovulatory follicles. However, the specific role of the FOS/AP-1 remains elusive. The present study determined the regulatory mechanisms driving the expression of FOS and its partners and functions of FOS using primary human granulosa/lutein cells (hGLC). hCG induced a biphasic increase in the expression of FOS, peaking at 1-3h and 12h. The levels of JUN proteins were also increased by hCG, with varying expression patterns. Co-immunoprecipitation analyses revealed that FOS is present as heterodimers with all JUN proteins. hCG immediately activated PKA and p42/44MAPK signaling pathways, and inhibitors for these pathways abolished hCG-induced increases in the levels of FOS, JUN, and JUNB. To identify the genes regulated by FOS, high throughput RNA sequencing was performed using hGLC treated with hCG ± T-5224 (FOS inhibitor). Sequencing data analysis revealed that FOS inhibition affects the expression of numerous genes, including a cluster of genes involved in the periovulatory process such as matrix remodeling, prostaglandin synthesis, glycolysis, and cholesterol biosynthesis. qPCR analysis verified hCG-induced, T-5224-regulated expression of a selection of genes involved in these processes. Consistently, hCG-induced increases in metabolic activities and cholesterol levels were suppressed by T-5224. This study unveiled potential downstream target genes of and a role for the FOS/AP-1 complex in metabolic changes and cholesterol biosynthesis in granulosa/lutein cells of human periovulatory follicles.

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