scholarly journals TET-Mediated Epigenetic Regulation in Immune Cell Development and Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Nikolas James Tsiouplis ◽  
David Wesley Bailey ◽  
Lilly Felicia Chiou ◽  
Fiona Jane Wissink ◽  
Ageliki Tsagaratou
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Immune Cell ◽  
Cell Development ◽  
Dna Demethylation ◽  
Oxidation Products ◽  
Specific Gene ◽  
Loss Of Function ◽  
Cell Fate Decisions ◽  
Tet Proteins

TET proteins oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidation products in DNA. The oxidized methylcytosines (oxi-mCs) facilitate DNA demethylation and are also novel epigenetic marks. TET loss-of-function is strongly associated with cancer; TET2 loss-of-function mutations are frequently observed in hematological malignancies that are resistant to conventional therapies. Importantly, TET proteins govern cell fate decisions during development of various cell types by activating a cell-specific gene expression program. In this review, we seek to provide a conceptual framework of the mechanisms that fine tune TET activity. Then, we specifically focus on the multifaceted roles of TET proteins in regulating gene expression in immune cell development, function, and disease.

scholarly journals C/EBPα determines hematopoietic cell fate in multipotential progenitor cells by inhibiting erythroid differentiation and inducing myeloid differentiation

Blood ◽  
2006 ◽  
Vol 107 (11) ◽  
pp. 4308-4316 ◽  
Author(s):  
Hyung Chan Suh ◽  
John Gooya ◽  
Katie Renn ◽  
Alan D. Friedman ◽  
Peter F. Johnson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Hematopoietic Cell ◽  
Myeloid Differentiation ◽  
Specific Gene ◽  
Erythroid Progenitors ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Conditional Expression ◽  
Murine Erythroleukemia

AbstractC/EBPα is an essential transcription factor required for myeloid differentiation. While C/EBPα can act as a cell fate switch to promote granulocyte differentiation in bipotential granulocyte-macrophage progenitors (GMPs), its role in regulating cell fate decisions in more primitive progenitors is not known. We found increased numbers of erythroid progenitors and erythroid cells in C/EBPα–/– fetal liver (FL). Also, enforced expression of C/EBPα in hematopoietic stem cells resulted in a loss of erythroid progenitors and an increase in myeloid cells by inhibition of erythroid development and inducing myeloid differentiation. Conditional expression of C/EBPα in murine erythroleukemia (MEL) cells induced myeloid-specific genes, while inhibiting erythroid-specific gene expression including erythropoietin receptor (EpoR), which suggests a novel mechanism to determine hematopoietic cell fate. Thus, C/EBPα functions in hematopoietic cell fate decisions by the dual actions of inhibiting erythroid and inducing myeloid gene expression in multipotential progenitors.

scholarly journals Expression of an activated rasD gene changes cell fate decisions during Dictyostelium development.

1997 ◽  
Vol 8 (2) ◽  
pp. 303-312 ◽  
Author(s):  
S A Louis ◽  
G B Spiegelman ◽  
G Weeks
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Cell Mass ◽  
Cell Formation ◽  
Specific Gene ◽  
Wild Type ◽  
Multicellular Development ◽  
Cell Fate Decisions ◽  
Prespore Cell

It has been previously demonstrated that the expression of an activated rasD gene in wild-type Dictyostelium cells results in formation of aggregates with multitips, instead of the normal single tips, and a block in further development. In an attempt to better understand the role of activated RasD development, we examined cell-type-specific gene expression in a strain stably expressing high levels of RasD[G12T]. We found that the expression of prestalk cell-specific genes ecmA and tagB was markedly enhanced, whereas the expression of the prespore cell-specific gene cotC was reduced to very low levels. When the fate of cells in the multitipped aggregate was monitored with an ecmA/lacZ fusion, it appeared that most of the cells eventually adopted prestalk gene expression characteristics. When mixtures of the [G12T]rasD cells and Ax3 cells were induced to differentiate, chimeric pseudoplasmodia were not formed. Thus, although the [G12T]rasD transformant had a marked propensity to form prestalk cells, it could not supply the prestalk cell population when mixed with wild-type cells. Both stalk and spore cell formation occurred in low cell density monolayers of the [G12T]rasD strain, suggesting that at least part of the inhibition of stalk and spore formation during multicellular development involved inhibitory cell interactions within the cell mass. Models for the possible role of rasD in development are discussed.

scholarly journals PRMT6 activates cyclin D1 expression in conjunction with the transcription factor LEF1

Oncogenesis ◽  
2021 ◽  
Vol 10 (5) ◽  
Author(s):  
Lucas Schneider ◽  
Stefanie Herkt ◽  
Lei Wang ◽  
Christine Feld ◽  
Josephine Wesely ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Transcription Factors ◽  
Cyclin D1 ◽  
Cell Fate ◽  
Target Genes ◽  
Specific Gene ◽  
Cell Fate Decisions ◽  
Rational Development ◽  
Differentiation And Proliferation

AbstractThe establishment of cell type specific gene expression by transcription factors and their epigenetic cofactors is central for cell fate decisions. Protein arginine methyltransferase 6 (PRMT6) is an epigenetic regulator of gene expression mainly through methylating arginines at histone H3. This way it influences cellular differentiation and proliferation. PRMT6 lacks DNA-binding capability but is recruited by transcription factors to regulate gene expression. However, currently only a limited number of transcription factors have been identified, which facilitate recruitment of PRMT6 to key cell cycle related target genes. Here, we show that LEF1 contributes to the recruitment of PRMT6 to the central cell cycle regulator CCND1 (Cyclin D1). We identified LEF1 as an interaction partner of PRMT6. Knockdown of LEF1 or PRMT6 reduces CCND1 expression. This is in line with our observation that knockdown of PRMT6 increases the number of cells in G1 phase of the cell cycle and decreases proliferation. These results improve the understanding of PRMT6 activity in cell cycle regulation. We expect that these insights will foster the rational development and usage of specific PRMT6 inhibitors for cancer therapy.

scholarly journals Super-Enhancers and CTCF in Early Embryonic Cell Fate Decisions

2021 ◽  
Vol 9 ◽  
Author(s):  
Puja Agrawal ◽  
Sridhar Rao
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Critical Role ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Cell Type ◽  
Mammalian Development ◽  
Cell Fate Decisions ◽  
Cell Type Specific ◽  
Early Mammalian Development

Cell fate decisions are the backbone of many developmental and disease processes. In early mammalian development, precise gene expression changes underly the rapid division of a single cell that leads to the embryo and are critically dependent on autonomous cell changes in gene expression. To understand how these lineage specifications events are mediated, scientists have had to look past protein coding genes to the cis regulatory elements (CREs), including enhancers and insulators, that modulate gene expression. One class of enhancers, termed super-enhancers, is highly active and cell-type specific, implying their critical role in modulating cell-type specific gene expression. Deletion or mutations within these CREs adversely affect gene expression and development and can cause disease. In this mini-review we discuss recent studies describing the potential roles of two CREs, enhancers and binding sites for CTCF, in early mammalian development.

Characterization of a Megakaryocyte-Specific Enhancer of the Key Hemopoietic Transcription Factor GATA1.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 834-834
Author(s):  
Boris Guyot ◽  
Kasumi Murai ◽  
Yuko Fujiwara ◽  
Veronica Valverde-Garduno ◽  
Michele Hammett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dna Binding ◽  
Transgenic Mice ◽  
Cell Fate ◽  
Red Cells ◽  
Specific Gene ◽  
Cell Fate Decisions

Abstract Specification and differentiation of the megakaryocyte and erythroid lineages from a common bipotential progenitor provides a well-studied model to dissect binary cell fate decisions. To understand how the distinct megakaryocyte- and erythroid-specific gene programs arise, we have examined the transcriptional regulation of the transcription factor GATA1, that is required for normal maturation of these two lineages. Megakaryocyte- and erythroid-specific mouse (m)GATA1 expression requires the mGata1 enhancer mHS-3.5. Within mHS-3.5, we previously showed that the 3′ 179 base pairs (bp) of mHS-3.5 are required for megakaryocyte but not red cell expression. Here, we show that mHS-3.5 binds key hemopoietic transcription factors in vivo (GATA1, SCL/TAL-1) and is required to maintain histone acetylation in the mGata1 locus in primary megakaryocytes. When deletional constructs containing mHS-3.5 were used to direct GATA1-LacZ reporter gene expression in transgenic mice, a 25 bp element within the 3′ 179bp in mHS-3.5, was critical for megakaryocyte expression. In vitro three uncharacterized DNA-binding activities A, B and C bind to the core of the 25 bp element, and these binding sites are conserved through evolution. Of these, only activity B is present in primary megakaryocytes but not red cells. Furthermore, mutation analysis in transgenic mice reveals that activity B is required for megakaryocyte-specific enhancer function. Bioinformatic analysis shows that sequence corresponding to the binding site for activity B is a previously unrecognised motif present in the cis-elements of other megakaryocyte-specific genes. In summary, we have identified a motif and a DNA-binding activity that are likely to be important in directing a megakaryocyte gene expression program distinct from that in red cells.

scholarly journals The Interplay Between Chromatin Architecture and Lineage-Specific Transcription Factors and the Regulation of Rag Gene Expression

2021 ◽  
Vol 12 ◽  
Author(s):  
Kazuko Miyazaki ◽  
Masaki Miyazaki
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Specific Gene ◽  
Cell Type ◽  
Cell Fate Decisions ◽  
Chromatin Architecture ◽  
Cell Type Specific

Cell type-specific gene expression is driven through the interplay between lineage-specific transcription factors (TFs) and the chromatin architecture, such as topologically associating domains (TADs), and enhancer-promoter interactions. To elucidate the molecular mechanisms of the cell fate decisions and cell type-specific functions, it is important to understand the interplay between chromatin architectures and TFs. Among enhancers, super-enhancers (SEs) play key roles in establishing cell identity. Adaptive immunity depends on the RAG-mediated assembly of antigen recognition receptors. Hence, regulation of the Rag1 and Rag2 (Rag1/2) genes is a hallmark of adaptive lymphoid lineage commitment. Here, we review the current knowledge of 3D genome organization, SE formation, and Rag1/2 gene regulation during B cell and T cell differentiation.

scholarly journals The DME demethylase regulates sporophyte gene expression, cell proliferation, differentiation, and meristem resurrection

2021 ◽  
Vol 118 (29) ◽  
pp. e2026806118
Author(s):  
Seohyun Kim ◽  
Jin-Sup Park ◽  
Jaehoon Lee ◽  
Kiseok Keith Lee ◽  
Ok-Sun Park ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Life Cycle ◽  
Growth And Development ◽  
Cellular Proliferation ◽  
De Novo ◽  
Dna Demethylation ◽  
Flowering Plant ◽  
Specific Gene ◽  
Loss Of Function

The flowering plant life cycle consists of alternating haploid (gametophyte) and diploid (sporophyte) generations, where the sporophytic generation begins with fertilization of haploid gametes. In Arabidopsis, genome-wide DNA demethylation is required for normal development, catalyzed by the DEMETER (DME) DNA demethylase in the gamete companion cells of male and female gametophytes. In the sporophyte, postembryonic growth and development are largely dependent on the activity of numerous stem cell niches, or meristems. Analyzing Arabidopsis plants homozygous for a loss-of-function dme-2 allele, we show that DME influences many aspects of sporophytic growth and development. dme-2 mutants exhibited delayed seed germination, variable root hair growth, aberrant cellular proliferation and differentiation followed by enhanced de novo shoot formation, dysregulation of root quiescence and stomatal precursor cells, and inflorescence meristem (IM) resurrection. We also show that sporophytic DME activity exerts a profound effect on the transcriptome of developing Arabidopsis plants, including discrete groups of regulatory genes that are misregulated in dme-2 mutant tissues, allowing us to potentially link phenotypes to changes in specific gene expression pathways. These results show that DME plays a key role in sporophytic development and suggest that DME-mediated active DNA demethylation may be involved in the maintenance of stem cell activities during the sporophytic life cycle in Arabidopsis.

scholarly journals GATA-targeted compounds modulate cardiac subtype cell differentiation in dual reporter stem cell line

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mika J. Välimäki ◽  
Robert S. Leigh ◽  
Sini M. Kinnunen ◽  
Alexander R. March ◽  
Ana Hernández de Sande ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Reporter Gene ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Cell Fate Decisions ◽  
Dual Reporter ◽  
Gene Regulatory ◽  
Reporter Gene Assays

AbstractBackgroundPharmacological modulation of cell fate decisions and developmental gene regulatory networks holds promise for the treatment of heart failure. Compounds that target tissue-specific transcription factors could overcome non-specific effects of small molecules and lead to the regeneration of heart muscle following myocardial infarction. Due to cellular heterogeneity in the heart, the activation of gene programs representing specific atrial and ventricular cardiomyocyte subtypes would be highly desirable. Chemical compounds that modulate atrial and ventricular cell fate could be used to improve subtype-specific differentiation of endogenous or exogenously delivered progenitor cells in order to promote cardiac regeneration.MethodsTranscription factor GATA4-targeted compounds that have previously shown in vivo efficacy in cardiac injury models were tested for stage-specific activation of atrial and ventricular reporter genes in differentiating pluripotent stem cells using a dual reporter assay. Chemically induced gene expression changes were characterized by qRT-PCR, global run-on sequencing (GRO-seq) and immunoblotting, and the network of cooperative proteins of GATA4 and NKX2-5 were further explored by the examination of the GATA4 and NKX2-5 interactome by BioID. Reporter gene assays were conducted to examine combinatorial effects of GATA-targeted compounds and bromodomain and extraterminal domain (BET) inhibition on chamber-specific gene expression.ResultsGATA4-targeted compounds 3i-1000 and 3i-1103 were identified as differential modulators of atrial and ventricular gene expression. More detailed structure-function analysis revealed a distinct subclass of GATA4/NKX2-5 inhibitory compounds with an acetyl lysine-like domain that contributed to ventricular cells (%Myl2-eGFP+). Additionally, BioID analysis indicated broad interaction between GATA4 and BET family of proteins, such as BRD4. This indicated the involvement of epigenetic modulators in the regulation of GATA-dependent transcription. In this line, reporter gene assays with combinatorial treatment of 3i-1000 and the BET bromodomain inhibitor (+)-JQ1 demonstrated the cooperative role of GATA4 and BRD4 in the modulation of chamber-specific cardiac gene expression.ConclusionsCollectively, these results indicate the potential for therapeutic alteration of cell fate decisions and pathological gene regulatory networks by GATA4-targeted compounds modulating chamber-specific transcriptional programs in multipotent cardiac progenitor cells and cardiomyocytes. The compound scaffolds described within this study could be used to develop regenerative strategies for myocardial regeneration.

scholarly journals Histone deacetylase 11 regulates oligodendrocyte-specific gene expression and cell development in OL-1 oligodendroglia cells

Glia ◽  
2009 ◽  
Vol 57 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Hedi Liu ◽  
Qichen Hu ◽  
A. Joseph D'ercole ◽  
Ping Ye
Keyword(s):  
Gene Expression ◽  
Histone Deacetylase ◽  
Cell Development ◽  
Specific Gene ◽  
Specific Gene Expression
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