scholarly journals An enriched network motif family regulates multistep cell fate transitions with restricted reversibility

2018 ◽  
Author(s):  
Yujie Ye ◽  
Jordan Bailey ◽  
Chunhe Li ◽  
Tian Hong
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Cell Fate ◽  
Biological Systems ◽  
T Cell Development ◽  
Cell Lineage ◽  
Design Principles ◽  
Cell Development ◽  
Gene Circuit ◽  
Gene Regulatory

AbstractMultistep cell fate transitions with stepwise changes of transcriptional profiles are common to many developmental, regenerative and pathological processes. The multiple intermediate cell lineage states can serve as differentiation checkpoints or branching points for channeling cells to more than one lineages. However, mechanisms underlying these transitions remain elusive. Here, we explored gene regulatory circuits that can generate multiple intermediate cellular states with stepwise modulations of transcription factors. With unbiased searching in the network topology space, we found a motif family containing a large set of networks can give rise to four attractors with the stepwise regulations of transcription factors, which limit the reversibility of three consecutive steps of the lineage transition. We found that there is an enrichment of these motifs in a transcriptional network controlling the early T cell development, and a mathematical model based on this network recapitulates multistep transitions in the early T cell lineage commitment. By calculating the energy landscape and minimum action paths for the T cell model, we quantified the stochastic dynamics of the critical factors in response to the differentiation signal with fluctuations. These results are in good agreement with experimental observations and they suggest the stable characteristics of the intermediate states in the T cell differentiation. These dynamical features may help to direct the cells to correct lineages during development. Our findings provide general design principles for multistep cell linage transitions and new insights into the early T cell development. The network motifs containing a large family of topologies can be useful for analyzing diverse biological systems with multistep transitions.Author summaryThe functions of cells are dynamically controlled in many biological processes including development, regeneration and disease progression. Cell fate transition, or the switch of cellular functions, often involves multiple steps. The intermediate stages of the transition provide the biological systems with the opportunities to regulate the transitions in a precise manner. These transitions are controlled by key regulatory genes of which the expression shows stepwise patterns, but how the interactions of these genes can determine the multistep processes were unclear. Here, we present a comprehensive analysis on the design principles of gene circuits that govern multistep cell fate transition. We found a large network family with common structural features that can generate systems with the ability to control three consecutive steps of the transition. We found that this type of networks is enriched in a gene circuit controlling the development of T lymphocyte, a crucial type of immune cells. We performed mathematical modeling using this gene circuit and we recapitulated the stepwise and irreversible loss of stem cell properties of the developing T lymphocytes. Our findings can be useful to analyze a wide range of gene regulatory networks controlling multistep cell fate transitions.

scholarly journals Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

2017 ◽  
Vol 114 (23) ◽  
pp. 5800-5807 ◽  
Author(s):  
William J. R. Longabaugh ◽  
Weihua Zeng ◽  
Jingli A. Zhang ◽  
Hiroyuki Hosokawa ◽  
Camden S. Jansen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Notch Signaling ◽  
Gene Regulatory Network ◽  
Cell Fate ◽  
Regulatory Network ◽  
T Cell Development ◽  
Cell Specification ◽  
Gene Regulatory

T-cell development from hematopoietic progenitors depends on multiple transcription factors, mobilized and modulated by intrathymic Notch signaling. Key aspects of T-cell specification network architecture have been illuminated through recent reports defining roles of transcription factors PU.1, GATA-3, and E2A, their interactions with Notch signaling, and roles of Runx1, TCF-1, and Hes1, providing bases for a comprehensively updated model of the T-cell specification gene regulatory network presented herein. However, the role of lineage commitment factor Bcl11b has been unclear. We use self-organizing maps on 63 RNA-seq datasets from normal and perturbed T-cell development to identify functional targets of Bcl11b during commitment and relate them to other regulomes. We show that both activation and repression target genes can be bound by Bcl11b in vivo, and that Bcl11b effects overlap with E2A-dependent effects. The newly clarified role of Bcl11b distinguishes discrete components of commitment, resolving how innate lymphoid, myeloid, and dendritic, and B-cell fate alternatives are excluded by different mechanisms.

scholarly journals The Route of Early T Cell Development: Crosstalk between Epigenetic and Transcription Factors

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1074
Author(s):  
Veronica Della Chiara ◽  
Lucia Daxinger ◽  
Frank J. T. Staal
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
Regulatory Networks ◽  
Developmental Stages ◽  
T Cell Development ◽  
Cell Lineage ◽  
Cell Development ◽  
Multipotent Progenitors ◽  
Epigenetic Regulators

Hematopoietic multipotent progenitors seed the thymus and then follow consecutive developmental stages until the formation of mature T cells. During this process, phenotypic changes of T cells entail stage-specific transcriptional programs that underlie the dynamic progression towards mature lymphocytes. Lineage-specific transcription factors are key drivers of T cell specification and act in conjunction with epigenetic regulators that have also been elucidated as crucial players in the establishment of regulatory networks necessary for proper T cell development. In this review, we summarize the activity of transcription factors and epigenetic regulators that together orchestrate the intricacies of early T cell development with a focus on regulation of T cell lineage commitment.

scholarly journals Aberrant T cell differentiation in the absence of Dicer

2005 ◽  
Vol 202 (2) ◽  
pp. 261-269 ◽  
Author(s):  
Stefan A. Muljo ◽  
K. Mark Ansel ◽  
Chryssa Kanellopoulou ◽  
David M. Livingston ◽  
Anjana Rao ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cell Fate ◽  
T Cell Development ◽  
Cell Lineage ◽  
Interferon Γ ◽  
Cell Development ◽  
Conditional Allele ◽  
Microrna Processing

Dicer is an RNaseIII-like enzyme that is required for generating short interfering RNAs and microRNAs. The latter have been implicated in regulating cell fate determination in invertebrates and vertebrates. To test the requirement for Dicer in cell-lineage decisions in a mammalian organism, we have generated a conditional allele of dicer-1 (dcr-1) in the mouse. Specific deletion of dcr-1 in the T cell lineage resulted in impaired T cell development and aberrant T helper cell differentiation and cytokine production. A severe block in peripheral CD8+ T cell development was observed upon dcr-1 deletion in the thymus. However, Dicer-deficient CD4+ T cells, although reduced in numbers, were viable and could be analyzed further. These cells were defective in microRNA processing, and upon stimulation they proliferated poorly and underwent increased apoptosis. Independent of their proliferation defect, Dicer-deficient helper T cells preferentially expressed interferon-γ, the hallmark effector cytokine of the Th1 lineage.

scholarly journals The TCF-1 and LEF-1 Transcription Factors Have Cooperative and Opposing Roles in T Cell Development and Malignancy

Immunity ◽  
2014 ◽  
Vol 40 (1) ◽  
pp. 166
Author(s):  
Shuyang Yu ◽  
Xinyuan Zhou ◽  
Farrah C. Steinke ◽  
Chengyu Liu ◽  
Shann-Ching Chen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development

scholarly journals Involvement of peripheral benzodiazepine receptors in the protection of hematopoietic cells against oxygen radical damage

Blood ◽  
1996 ◽  
Vol 87 (8) ◽  
pp. 3170-3178 ◽  
Author(s):  
P Carayon ◽  
M Portier ◽  
D Dussossoy ◽  
A Bord ◽  
G Petitpretre ◽  
...  
Keyword(s):  
T Cell ◽  
Benzodiazepine Receptors ◽  
T Cell Development ◽  
Cell Lineage ◽  
Benzodiazepine Receptor ◽  
Cell Development ◽  
Jurkat Cells ◽  
Phagocytic Cells ◽  
Radical Oxygen Species ◽  
Healthy Donors

Several putative functions have been attributed to the peripheral benzodiazepine receptor (PBR), but its precise physiologic role has not been elucidated. In the present study, we investigated PBR function by quantifying this receptor in leukocyte subsets from healthy donors and in leukemic blasts from lymphoid and myeloid lineages. Using a monoclonal antibody (MoAb) directed against the human PBR and a quantitative flow cytometric assay, we found that phagocytic cells from healthy donors displayed a higher level of PBRs than lymphocytes or natural killer (NK) cells. Among the lymphoid lineage, thymocytes and IgD-negative B cells expressed the lowest levels. However, because of the wide heterogeneity of PBR levels among 42 acute or chronic lymphoid and myeloid leukemias, it was not possible to assign PBR expression to a stage of maturation or a cell lineage. Although the PBR displayed a mitochondrial subcellular localization, its expression was not correlated with the mitochondrial content, suggesting a modulation of PBR density at the level of the mitochondria. This modulation was confirmed when we studied in detail the PBR expression during T-cell development by both flow cytometry and confocal microscopy. We found that the PBR was expressed with a bimodal profile during T-cell development, identical to the one observed with the proto-oncogene, Bcl- 2. The high similarity in the expression of both the PBR and the Bcl-2 proto-oncogene in T-cell and B-cell subsets, their common mitochondrial localization, and the observation of high quantities of PBR in phagocytic cells, which are known to produce high levels of radical oxygen species, suggested that PBRs may participate in an antioxidant pathway. Indeed, a strong correlation was established between the ability of hematopoietic cell lines to resist H202 cytotoxicity and their level of PBR expression. Demonstration of the role of PBR in the protection against H202 was obtained by transfecting JURKAT cells with the human PBR cDNA. Transfected cells exhibited increased resistance to H202 compared with wild-type cells, suggesting that PBR may prevent mitochondria from radical damages and thereby modulate apoptosis in the hematopoietic system.

scholarly journals Functions of E2A-HEB Heterodimers in T-Cell Development Revealed by a Dominant Negative Mutation of HEB

2000 ◽  
Vol 20 (18) ◽  
pp. 6677-6685 ◽  
Author(s):  
Robert J. Barndt ◽  
Meifang Dai ◽  
Yuan Zhuang
Keyword(s):  
T Cell ◽  
Target Genes ◽  
T Cell Development ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Cell Development ◽  
Dominant Negative ◽  
Helix Loop Helix ◽  
Dominant Negative Mutation ◽  
Bhlh Proteins

ABSTRACT Lymphocyte development and differentiation are regulated by the basic helix-loop-helix (bHLH) transcription factors encoded by theE2A and HEB genes. These bHLH proteins bind to E-box enhancers in the form of homodimers or heterodimers and, consequently, activate transcription of the target genes. E2A homodimers are the predominant bHLH proteins present in B-lineage cells and are shown genetically to play critical roles in B-cell development. E2A-HEB heterodimers, the major bHLH dimers found in thymocyte extracts, are thought to play a similar role in T-cell development. However, disruption of either the E2A or HEBgene led to only partial blocks in T-cell development. The exact role of E2A-HEB heterodimers and possibly the E2A and HEB homodimers in T-cell development cannot be distinguished in simple disruption analysis due to a functional compensation from the residual bHLH homodimers. To further define the function of E2A-HEB heterodimers, we generated and analyzed a dominant negative allele of HEB, which produces a physiological amount of HEB proteins capable of forming nonfunctional heterodimers with E2A proteins. Mice carrying this mutation show a stronger and earlier block in T-cell development than HEB complete knockout mice. The developmental block is specific to the α/β T-cell lineage at a stage before the completion of V(D)J recombination at the TCRβ gene locus. This defect is intrinsic to the T-cell lineage and cannot be rescued by expression of a functional T-cell receptor transgene. These results indicate that E2A-HEB heterodimers play obligatory roles both before and after TCRβ gene rearrangement during the α/β lineage T-cell development.

scholarly journals The TCF-1 and LEF-1 Transcription Factors Have Cooperative and Opposing Roles in T Cell Development and Malignancy

Immunity ◽  
2012 ◽  
Vol 37 (5) ◽  
pp. 813-826 ◽  
Author(s):  
Shuyang Yu ◽  
Xinyuan Zhou ◽  
Farrah C. Steinke ◽  
Chengyu Liu ◽  
Shann-Ching Chen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development

scholarly journals Foxo Transcription Factors Control Regulatory T Cell Development and Function

Immunity ◽  
2011 ◽  
Vol 34 (1) ◽  
pp. 135
Author(s):  
Yann M. Kerdiles ◽  
Erica L. Stone ◽  
Daniel R. Beisner ◽  
Maureen A. McGargill ◽  
Irene L. Ch'en ◽  
...  
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Regulatory T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Foxo Transcription Factors ◽  
And Function

The Histone Acetyltransferase CBP Is Essential for Conventional T Cell Development.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2294-2294
Author(s):  
Tomofusa Fukuyama ◽  
Fayçal Boussouar ◽  
Lawryn H. Kasper ◽  
Jan M. van Deursen ◽  
Paul K. Brindle
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
Chemokine Receptors ◽  
Fas Ligand ◽  
T Cell Development ◽  
Cell Development ◽  
Mutant Mice ◽  
Effector Memory ◽  
Creb Binding Protein ◽  
Cell Fate Decisions

Abstract Defining the epigenetic mechanisms (e.g. chromatin modifications) that underlie T cell fate decisions is a major challenge. The transcriptional coactivators CREB binding protein (CBP) and the closely related p300 comprise a two-member family of histone/protein acetyltransferases that interact with over 50 T lymphocyte-essential transcriptional regulators. Rather than having distinct regulatory roles, CBP and p300 are often thought to confer utilitarian transactivation and histone modifying functions to transcription factors that mediate T cell fate. In contrast to this view, we show here that CBP acts uniquely in conventional T cell development. Inactivation of CBP, but not p300, starting at the double negative stage of T cell development yielded thymocytes with partial activation of an effector/memory- or innate-T cell program. CD8SP thymocytes from CBP mutant mice expressed genes that define professional CD8 cells such as Il-2/Il-15 receptor β chain, granzyme A, interferon γ (Ifnγ), Fas ligand, perforin, and the chemokine receptors Ccr5, and Cxcr3. CD4SP thymocytes from CBP mutant mice also expressed effector genes such as Ifnγ, Il-4, and Ccr5. In addition, CD8SP and CD4SP thymocytes from CBP mutant mice produced Ifnγ protein when the cells were stimulated with phorbol ester and ionomycin. Mechanistically, loss of CBP acted cell non-autonomously to induce the expression of the CD8 T cell master regulatory transcription factor eomesodermin (Eomes). This suggests that CBP in thymocytes or T cells controls an extracellular factor that helps demarcate conventional naïve T cell development in the thymus from effector/memory T cell differentiation in the periphery.

Sign in / Sign up

Export Citation Format

Share Document