ERG orchestrates chromatin interactions to drive prostate cell fate reprogramming

AbstractWhile cancer is commonly perceived as a disease of dedifferentiation, the hallmark of early stage prostate cancer is paradoxically the loss of more plastic basal cells and the abnormal proliferation of more differentiated secretory luminal cells. However, the mechanism of prostate cancer pro-luminal differentiation is largely unknown. Through integrating analysis of the transcription factors (TFs) from 806 human prostate cancers, we have identified that ERG highly correlated with prostate cancer luminal subtyping. ERG overexpression in luminal epithelial cells inhibits its normal plasticity to transdifferentiate into basal lineage and ERG supersedes PTEN-loss which favors basal differentiation. ERG knock-out disrupted prostate cell luminal differentiation, whereas AR knock-out had no such effects. Trp63 is a known master regulator of prostate basal lineage. Through analysis of 3D chromatin architecture, we found that ERG binds and inhibits the enhancer activity and chromatin looping of a Trp63 distal enhancer, thereby silencing its gene expression. Specific deletion of the distal ERG binding site resulted in the loss of ERG-mediated inhibition of basal differentiation. Thus, ERG orchestrates chromatin interactions and regulates prostate cell lineage toward pro-luminal program, as its fundamental role on lineage differentiation in prostate cancer initiation.

Download Full-text

EBF1 is expressed in pericytes and contributes to pericyte cell commitment

Histochemistry and Cell Biology ◽

10.1007/s00418-021-02015-7 ◽

2021 ◽

Author(s):

Francesca Pagani ◽

Elisa Tratta ◽

Patrizia Dell’Era ◽

Manuela Cominelli ◽

Pietro Luigi Poliani

Keyword(s):

Stem Cells ◽

Endothelial Cells ◽

Mesenchymal Stem Cells ◽

B Cell ◽

Cell Fate ◽

Early Stage ◽

Cell Lineage ◽

Cell Maturation ◽

Cell Commitment

AbstractEarly B-cell factor-1 (EBF1) is a transcription factor with an important role in cell lineage specification and commitment during the early stage of cell maturation. Originally described during B-cell maturation, EBF1 was subsequently identified as a crucial molecule for proper cell fate commitment of mesenchymal stem cells into adipocytes, osteoblasts and muscle cells. In vessels, EBF1 expression and function have never been documented. Our data indicate that EBF1 is highly expressed in peri-endothelial cells in both tumor vessels and in physiological conditions. Immunohistochemistry, quantitative reverse transcription polymerase chain reaction (RT-qPCR) and fluorescence-activated cell sorting (FACS) analysis suggest that EBF1-expressing peri-endothelial cells represent bona fide pericytes and selectively express well-recognized markers employed in the identification of the pericyte phenotype (SMA, PDGFRβ, CD146, NG2). This observation was also confirmed in vitro in human placenta-derived pericytes and in human brain vascular pericytes (HBVP). Of note, in accord with the key role of EBF1 in the cell lineage commitment of mesenchymal stem cells, EBF1-silenced HBVP cells showed a significant reduction in PDGFRβ and CD146, but not CD90, a marker mostly associated with a prominent mesenchymal phenotype. Moreover, the expression levels of VEGF, angiopoietin-1, NG2 and TGF-β, cytokines produced by pericytes during angiogenesis and linked to their differentiation and activation, were also significantly reduced. Overall, the data suggest a functional role of EBF1 in the cell fate commitment toward the pericyte phenotype.

Download Full-text

A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment

10.1101/318675 ◽

2018 ◽

Cited By ~ 1

Author(s):

Kenneth K.H. Ng ◽

Mary A. Yui ◽

Arnav Mehta ◽

Sharmayne Siu ◽

Blythe Irwin ◽

...

Keyword(s):

T Cell ◽

Cell Fate ◽

Fluorescent Proteins ◽

Cell Lineage ◽

Distal Enhancer ◽

Epigenetic Switch ◽

Individual Gene ◽

Cell Fate Decisions ◽

Genetic Perturbations ◽

Tightly Coupled

SummaryCell fate decisions occur through the switch-like, irreversible activation of fate-specifying genes. These activation events are often assumed to be tightly-coupled to changes in upstream transcription factors, but could also be constrained by cis-epigenetic mechanisms at individual gene loci. Here, we studied the activation of Bcl11b, which controls T-cell fate commitment. To disentangle cis and trans effects, we generated mice where two Bcl11b copies are tagged with distinguishable fluorescent proteins. Quantitative live microscopy of progenitors from these mice revealed that Bcl11b turned on after a stochastic delay averaging multiple days, which varied not only between cells but also between Bcl11b alleles within the same cell. Genetic perturbations, together with mathematical modeling, showed that a distal enhancer controls the rate of epigenetic activation, while a parallel Notch-dependent trans-acting step stimulates expression from activated loci. These results show that developmental fate transitions can be controlled by stochastic cis-acting events on individual loci.

Download Full-text

A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment

eLife ◽

10.7554/elife.37851 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 16

Author(s):

Kenneth KH Ng ◽

Mary A Yui ◽

Arnav Mehta ◽

Sharmayne Siu ◽

Blythe Irwin ◽

...

Keyword(s):

T Cell ◽

Cell Fate ◽

Fluorescent Proteins ◽

Cell Lineage ◽

Distal Enhancer ◽

Epigenetic Switch ◽

Individual Gene ◽

Cis Acting ◽

Cell Fate Decisions ◽

Tightly Coupled

Cell fate decisions occur through the switch-like, irreversible activation of fate-specifying genes. These activation events are often assumed to be tightly coupled to changes in upstream transcription factors, but could also be constrained by cis-epigenetic mechanisms at individual gene loci. Here, we studied the activation of Bcl11b, which controls T-cell fate commitment. To disentangle cis and trans effects, we generated mice where two Bcl11b copies are tagged with distinguishable fluorescent proteins. Quantitative live microscopy of progenitors from these mice revealed that Bcl11b turned on after a stochastic delay averaging multiple days, which varied not only between cells but also between Bcl11b alleles within the same cell. Genetic perturbations, together with mathematical modeling, showed that a distal enhancer controls the rate of epigenetic activation, while a parallel Notch-dependent trans-acting step stimulates expression from activated loci. These results show that developmental fate transitions can be controlled by stochastic cis-acting events on individual loci.

Download Full-text

Positional cues specify and maintain aleurone cell fate in maize endosperm development

Development ◽

10.1242/dev.127.18.4039 ◽

2000 ◽

Vol 127 (18) ◽

pp. 4039-4048 ◽

Cited By ~ 3

Author(s):

P.W. Becraft ◽

Y. Asuncion-Crabb

Keyword(s):

Cell Fate ◽

Early Stage ◽

Cell Lineage ◽

Chromosome Breakage ◽

Endosperm Development ◽

Loss Of Function ◽

Maize Endosperm ◽

Starchy Endosperm ◽

Aleurone Cell ◽

Aleurone Cells

A genetic analysis of maize aleurone development was conducted. Cell lineage was examined by simultaneously marking cells with C1 for anthocyanin pigmentation in the aleurone and wx1 for amylose synthesis in the starchy endosperm. The aleurone and starchy endosperm share a common lineage throughout development indicating that positional cues specify aleurone fate. Mutants in dek1 block aleurone formation at an early stage and cause peripheral endosperm cells to develop as starchy endosperm. Revertant sectors of a transposon-induced dek1 allele showed that peripheral endosperm cells remain competent to differentiate as aleurone cells until late in development. Ds-induced chromosome breakage was used to generate Dek1 loss-of-function sectors. Events occurring until late development caused aleurone cells to switch fate to starchy endosperm indicating that cell fate is not fixed. Thus, positional cues are required to specify and maintain aleurone fate and Dek1 function is required to respond to these cues. An analysis of additional mutants that disrupt aleurone differentiation suggests a hierarchy of gene functions to specify aleurone cell fate and then control aleurone differentiation. These mutants disrupt aleurone differentiation in reproducible patterns suggesting a relationship to endosperm pattern formation.

Download Full-text

Notch1 Deficiency Dissociates the Intrathymic Development of Dendritic Cells and T Cells

Journal of Experimental Medicine ◽

10.1084/jem.191.7.1085 ◽

2000 ◽

Vol 191 (7) ◽

pp. 1085-1094 ◽

Cited By ~ 119

Author(s):

Freddy Radtke ◽

Isabel Ferrero ◽

Anne Wilson ◽

Rosemary Lees ◽

Michel Aguet ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cell Fate ◽

Early Stage ◽

Cell Lineage ◽

Absolute Number ◽

Competitive Situation ◽

Surface Receptors ◽

Selection Of

Thymic dendritic cells (DCs) form a discrete subset of bone marrow (BM)-derived cells, the function of which is to mediate negative selection of autoreactive thymocytes. The developmental origin of thymic DCs remains controversial. Although cell transfer studies support a model in which T cells and thymic DCs develop from the same intrathymic pluripotential precursor, it remains possible that these two types of cells develop from independent intrathymic precursors. Notch proteins are cell surface receptors involved in the regulation of cell fate specification. We have recently reported that T cell development in inducible Notch1-deficient mice is severely impaired at an early stage, before the expression of T cell lineage markers. To investigate whether development of thymic DCs also depends on Notch1, we have constructed mixed BM chimeric mice. We report here that thymic DC development from Notch1−/− BM precursors is absolutely normal (in terms of absolute number and phenotype) in this competitive situation, despite the absence of Notch1−/− T cells. Furthermore, we find that peripheral DCs and Langerhans cells are also not affected by Notch1 deficiency. Our results demonstrate that the development of DCs is totally independent of Notch1 function, and strongly suggest a dissociation between intrathymic T cell and DC precursors.

Download Full-text