scholarly journals DNA demethylation switches the drivers of Foxp3 expression to maintain regulatory T cell identity

2020 ◽  
Author(s):  
Jun Li ◽  
Beisi Xu ◽  
Xinying Zong ◽  
Minghong He ◽  
Yiping Fan ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Cell Fate ◽  
Regulatory T Cell ◽  
Molecular Basis ◽  
Foxp3 Expression ◽  
Chromatin Accessibility ◽  
Dna Demethylation ◽  
Biological Processes ◽  
Regulatory Mode

ABSTRACTMaintenance of differentiated cellular states is crucial for numerous biological processes, yet its molecular basis remains unclear. Here, we investigate how mechanistically regulatory T (Treg) cell fate is “locked in” during lineage commitment via transcriptional regulation of its lineage-specifying factor Foxp3. Tet-mediated DNA demethylation ofFoxp3enhancer CNS2 was proposed to be a key mechanism maintaining Foxp3 transcription. However, this model has not been directly tested. Therefore, we integrated genetic, pharmacological, and epigenetic approaches to examine the function and mechanism of DNA demethylation in Treglineage maintenance. We observed an abrupt switch of the transcriptional drivers of Foxp3 upon DNA demethylation, which was abolished by CNS2 deficiency. Demethylation of CNS2 increased chromatin accessibility and protein binding, conferring on Tregfate substantial resistance to adverse environments. Thus, our study consolidated the role of DNA demethylation in stabilizing Foxp3 expression incisand revealed a novel regulatory mode governing Tregidentity.

scholarly journals Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation

2014 ◽  
Vol 111 (14) ◽  
pp. 5289-5294 ◽  
Author(s):  
H. Morikawa ◽  
N. Ohkura ◽  
A. Vandenbon ◽  
M. Itoh ◽  
S. Nagao-Sato ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
T Cell ◽  
Regulatory T Cell ◽  
Foxp3 Expression ◽  
Epigenetic Changes

The neuronal network of the endogenous clock

e-Neuroforum ◽  
2010 ◽  
Vol 16 (1) ◽  
Author(s):  
Charlotte Förster
Keyword(s):  
Molecular Basis ◽  
Clock Genes ◽  
Fruit Fly ◽  
Biological Processes ◽  
Rhythm Generation ◽  
The Metabolic Syndrome ◽  
Clock Network ◽  
Endogenous Clock ◽  
The Brain

AbstractEndogenous clocks control the rhythm of many biological processes. Malfunction of endogenous clocks in humans can lead to various diseases as sleep disorders, depres­sions, the metabolic syndrome and cancer. All animals have a main clock in the brain. This clock comprises a network of clock neurons that communicate with each other. In each clock neuron, conserved clock genes and pro­teins interact in to generate a molecular os­cillation. The molecular basis of this rhythm generation as well as the anatomy of the neuronal clock network is best investigated in the fruit fly Drosophila melanogaster. In the little fly, clock genes can be shut down in specific clock neurons. Furthermore, specific clock neurons can be electrically silenced and the rhythmic behaviour of such manipulated flies can be studied. A flurry of recent studies has begun to identify the role of specific clock neurons in the clock network, and these find­ings are helping to understand the basic neu­ronal mechanisms of endogenous clocks.

scholarly journals Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate

Nature ◽  
2010 ◽  
Vol 463 (7282) ◽  
pp. 808-812 ◽  
Author(s):  
Ye Zheng ◽  
Steven Josefowicz ◽  
Ashutosh Chaudhry ◽  
Xiao P. Peng ◽  
Katherine Forbush ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
Regulatory T Cell ◽  
Foxp3 Gene ◽  
Dna Elements

scholarly journals Structural evidence for Scc4-dependent localization of cohesin loading

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Stephen M Hinshaw ◽  
Vasso Makrantoni ◽  
Alastair Kerr ◽  
Adèle L Marston ◽  
Stephen C Harrison
Keyword(s):  
Crystal Structure ◽  
Transcriptional Regulation ◽  
Cell Division ◽  
Molecular Basis ◽  
Developmental Defects ◽  
Chromosome Missegregation ◽  
Sister Chromatids ◽  
Chromatid Cohesion ◽  
Multicellular Organisms

The cohesin ring holds newly replicated sister chromatids together until their separation at anaphase. Initiation of sister chromatid cohesion depends on a separate complex, Scc2NIPBL/Scc4Mau2 (Scc2/4), which loads cohesin onto DNA and determines its localization across the genome. Proper cohesin loading is essential for cell division, and partial defects cause chromosome missegregation and aberrant transcriptional regulation, leading to severe developmental defects in multicellular organisms. We present here a crystal structure showing the interaction between Scc2 and Scc4. Scc4 is a TPR array that envelops an extended Scc2 peptide. Using budding yeast, we demonstrate that a conserved patch on the surface of Scc4 is required to recruit Scc2/4 to centromeres and to build pericentromeric cohesion. These findings reveal the role of Scc4 in determining the localization of cohesin loading and establish a molecular basis for Scc2/4 recruitment to centromeres.

scholarly journals Stag1 and Stag2 regulate cell fate decisions in hematopoiesis through non-redundant topological control

2019 ◽  
Author(s):  
Aaron D. Viny ◽  
Robert L. Bowman ◽  
Yu Liu ◽  
Vincent-Philippe Lavallée ◽  
Shira E. Eisman ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cell Lineage ◽  
Chromatin Accessibility ◽  
Lineage Specification ◽  
Hematopoietic Stem ◽  
Chip Sequencing ◽  
Cell Fate Decisions ◽  
Transcriptional Dysregulation ◽  
Topologically Associated Domains

AbstractTranscriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show Stag2 deletion in hematopoietic stem/progenitor cells (HSPC) results in altered hematopoietic function, increased self-renewal, and impaired differentiation. ChIP-sequencing revealed that while Stag2 and Stag1 can bind the same loci, a component of Stag2 binding sites are unoccupied by Stag1 even in Stag2-deficient HSPCs. While concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to blunted HSPC commitment to the B-cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation.One Sentence SummaryStag1 rescues topologically associated domains in the absence of Stag2, but cannot restore chromatin architecture required for hematopoietic lineage commitment

scholarly journals Role of Non-Coding RNAs in Post-Transcriptional Regulation of Lung Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Dharmendra Kumar Soni ◽  
Roopa Biswas
Keyword(s):  
Transcriptional Regulation ◽  
Lung Diseases ◽  
Fine Tuning ◽  
Chronic Obstructive ◽  
Biological Processes ◽  
Obstructive Pulmonary Disease ◽  
Non Coding Rnas ◽  
Specific Tissue ◽  
Post Transcriptional Regulation

Non-coding RNAs (ncRNAs), notably microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), have recently gained increasing consideration because of their versatile role as key regulators of gene expression. They adopt diverse mechanisms to regulate transcription and translation, and thereby, the function of the protein, which is associated with several major biological processes. For example, proliferation, differentiation, apoptosis, and metabolic pathways demand fine-tuning for the precise development of a specific tissue or organ. The deregulation of ncRNA expression is concomitant with multiple diseases, including lung diseases. This review highlights recent advances in the post-transcriptional regulation of miRNAs and lncRNAs in lung diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, and idiopathic pulmonary fibrosis. Further, we also discuss the emerging role of ncRNAs as biomarkers as well as therapeutic targets for lung diseases. However, more investigations are required to explore miRNAs and lncRNAs interaction, and their function in the regulation of mRNA expression. Understanding these mechanisms might lead to early diagnosis and the development of novel therapeutics for lung diseases.

scholarly journals The Complexity of TET2 Functions in Pluripotency and Development

2021 ◽  
Vol 8 ◽  
Author(s):  
Vera Garcia-Outeiral ◽  
Cristina de la Parte ◽  
Miguel Fidalgo ◽  
Diana Guallar
Keyword(s):  
Transcriptional Regulation ◽  
Cell Fate ◽  
Normal Development ◽  
Tissue Homeostasis ◽  
Biological Processes ◽  
Chemical Modifications ◽  
Dna And Rna ◽  
Genome Regulation ◽  
Cellular Phenotypes ◽  
Post Transcriptional Regulation

Ten-eleven translocation-2 (TET2) is a crucial driver of cell fate outcomes in a myriad of biological processes, including embryonic development and tissue homeostasis. TET2 catalyzes the demethylation of 5-methylcytosine on DNA, affecting transcriptional regulation. New exciting research has provided evidence for TET2 catalytic activity in post-transcriptional regulation through RNA hydroxymethylation. Here we review the current understanding of TET2 functions on both DNA and RNA, and the influence of these chemical modifications in normal development and pluripotency contexts, highlighting TET2 versatility in influencing genome regulation and cellular phenotypes.

Dichotomous role of TGF-β controls inducible regulatory T-cell fate in allergic airway disease through Smad3 and TGF-β–activated kinase 1

2020 ◽  
Vol 145 (3) ◽  
pp. 933-946.e4
Author(s):  
Anthony Joetham ◽  
Michaela Schedel ◽  
Fangkun Ning ◽  
Meiqin Wang ◽  
Katsuyuki Takeda ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
Regulatory T Cell ◽  
Airway Disease ◽  
Allergic Airway Disease

scholarly journals Unravelling HP1 functions: post-transcriptional regulation of stem cell fate

Chromosoma ◽  
2021 ◽  
Author(s):  
Assunta Maria Casale ◽  
Ugo Cappucci ◽  
Lucia Piacentini
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Stem Cell ◽  
Cell Fate ◽  
Regulation Of Gene Expression ◽  
Telomere Maintenance ◽  
Chromosomal Protein ◽  
Heterochromatin Protein 1 ◽  
Post Transcriptional Regulation

AbstractHeterochromatin protein 1 (HP1) is a non-histone chromosomal protein first identified in Drosophila as a major component of constitutive heterochromatin, required for stable epigenetic gene silencing in many species including humans. Over the years, several studies have highlighted additional roles of HP1 in different cellular processes including telomere maintenance, DNA replication and repair, chromosome segregation and, surprisingly, positive regulation of gene expression. In this review, we briefly summarize past research and recent results supporting the unexpected and emerging role of HP1 in activating gene expression. In particular, we discuss the role of HP1 in post-transcriptional regulation of mRNA processing because it has proved decisive in the control of germline stem cells homeostasis in Drosophila and has certainly added a new dimension to our understanding on HP1 targeting and functions in epigenetic regulation of stem cell behaviour.

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