scholarly journals Precise developmental regulation of Ets family transcription factors during specification and commitment to the T cell lineage

Development ◽  
1999 ◽  
Vol 126 (14) ◽  
pp. 3131-3148 ◽  
Author(s):  
M.K. Anderson ◽  
G. Hernandez-Hoyos ◽  
R.A. Diamond ◽  
E.V. Rothenberg
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
B Cell ◽  
Developmental Stages ◽  
Developmental Regulation ◽  
Hematopoietic Cells ◽  
Cell Lineage ◽  
Lineage Commitment ◽  
Lineage Specification ◽  
Ets Family

Ets family transcription factors control the expression of a large number of genes in hematopoietic cells. Here we show strikingly precise differential expression of a subset of these genes marking critical, early stages of mouse lymphocyte cell-type specification. Initially, the Ets family member factor Erg was identified during an arrayed cDNA library screen for genes encoding transcription factors expressed specifically during T cell lineage commitment. Multiparameter fluorescence-activated cell sorting for over a dozen cell surface markers was used to isolate 18 distinct primary-cell populations representing discrete T cell and B cell developmental stages, pluripotent lymphoid precursors, immature NK-like cells and myeloid hematopoietic cells. These populations were monitored for mRNA expression of the Erg, Ets-1, Ets-2, Fli-1, Tel, Elf-1, GABPalpha, PU.1 and Spi-B genes. The earliest stages in T cell differentiation show particularly dynamic Ets family gene regulation, with sharp transitions in expression correlating with specification and commitment events. Ets, Spi-B and PU.1 are expressed in these stages but not by later T-lineage cells. Erg is induced during T-lineage specification and then silenced permanently, after commitment, at the beta-selection checkpoint. Spi-B is transiently upregulated during commitment and then silenced at the same stage as Erg. T-lineage commitment itself is marked by repression of PU.1, a factor that regulates B-cell and myeloid genes. These results show that the set of Ets factors mobilized during T-lineage specification and commitment is different from the set that maintains T cell gene expression during thymocyte repertoire selection and in all classes of mature T cells.

scholarly journals Stage-specific action of Runx1 and GATA3 controls silencing of PU.1 expression in mouse pro–T cells

2021 ◽  
Vol 218 (8) ◽  
Author(s):  
Hiroyuki Hosokawa ◽  
Maria Koizumi ◽  
Kaori Masuhara ◽  
Maile Romero-Wolf ◽  
Tomoaki Tanaka ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Transcription Factors ◽  
T Cell ◽  
Cell Line ◽  
Functional Site ◽  
Lineage Commitment ◽  
Factor Binding ◽  
Ets Family ◽  
Intron 2

PU.1 (encoded by Spi1), an ETS-family transcription factor with many hematopoietic roles, is highly expressed in the earliest intrathymic T cell progenitors but must be down-regulated during T lineage commitment. The transcription factors Runx1 and GATA3 have been implicated in this Spi1 repression, but the basis of the timing was unknown. We show that increasing Runx1 and/or GATA3 down-regulates Spi1 expression in pro–T cells, while deletion of these factors after Spi1 down-regulation reactivates its expression. Leveraging the stage specificities of repression and transcription factor binding revealed an unconventional but functional site in Spi1 intron 2. Acute Cas9-mediated deletion or disruption of the Runx and GATA motifs in this element reactivates silenced Spi1 expression in a pro–T cell line, substantially more than disruption of other candidate elements, and counteracts the repression of Spi1 in primary pro–T cells during commitment. Thus, Runx1 and GATA3 work stage specifically through an intronic silencing element in mouse Spi1 to control strength and maintenance of Spi1 repression during T lineage commitment.

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 Permissive roles of cytokines interleukin-7 and Flt3 ligand in mouse B-cell lineage commitment

2016 ◽  
Vol 113 (50) ◽  
pp. E8122-E8130 ◽  
Author(s):  
Lilly von Muenchow ◽  
Llucia Alberti-Servera ◽  
Fabian Klein ◽  
Giuseppina Capoferri ◽  
Daniela Finke ◽  
...  
Keyword(s):  
B Cell ◽  
Hematopoietic Cells ◽  
Cell Lineage ◽  
Cell Development ◽  
B Cell Development ◽  
Lineage Commitment ◽  
Flt3 Ligand ◽  
Interleukin 7 ◽  
Cell Commitment ◽  
Deficient Mice

Hematopoietic cells are continuously generated throughout life from hematopoietic stem cells, thus making hematopoiesis a favorable system to study developmental cell lineage commitment. The main factors incorporating environmental signals to developing hematopoietic cells are cytokines, which regulate commitment of hematopoietic progenitors to the different blood lineages by acting either in an instructive or a permissive manner. Fms-like tyrosine kinase-3 (Flt3) ligand (FL) and Interleukin-7 (IL-7) are cytokines pivotal for B-cell development, as manifested by the severely compromised B-cell development in their absence. However, their precise role in regulating B-cell commitment has been the subject of debate. In the present study we assessed the rescue of B-cell commitment in mice lacking IL-7 but simultaneously overexpressing FL. Results obtained demonstrate that FL overexpression in IL-7–deficient mice rescues B-cell commitment, resulting in significant Ebf1 and Pax5 expression in Ly6D+CD135+CD127+CD19− precursors and subsequent generation of normal numbers of CD19+ B-cell progenitors, therefore indicating that IL-7 can be dispensable for commitment to the B-cell lineage. Further analysis of Ly6D+CD135+CD127+CD19− progenitors in IL-7– or FL-deficient mice overexpressing Bcl2, as well as in IL-7 transgenic mice suggests that both FL and IL-7 regulate B-cell commitment in a permissive manner: FL by inducing proliferation of Ly6D+CD135+CD127+CD19− progenitors and IL-7 by providing survival signals to these progenitors.

Signalling circuits that direct early B-cell development

2019 ◽  
Vol 476 (5) ◽  
pp. 769-778 ◽  
Author(s):  
Georg Petkau ◽  
Martin Turner
Keyword(s):  
B Cells ◽  
B Cell ◽  
Developmental Stages ◽  
Cell Lineage ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lineage Specification ◽  
Interleukin 7 ◽  
Proliferation And Apoptosis ◽  
B Cell Precursors

Abstract In mammals, the B-cell lineage arises from pluripotent progenitors in the bone marrow. During their development, B-cells undergo lineage specification and commitment, followed by expansion and selection. These processes are mediated by regulated changes in gene expression programmes, rearrangements of immunoglobulin (Ig) genes, and well-timed rounds of proliferation and apoptosis. Many of these processes are initiated by environmental factors including cytokines, chemokines, and cell–cell contacts. Developing B-cells process these environmental cues into stage-specific functions via signalling pathways including the PI3K, MAPK, or JAK-STAT pathway. The cytokines FLT3-Ligand and c-Kit-Ligand are important for the early expansion of the B-cell precursors at different developmental stages and conditions. Interleukin 7 is essential for commitment to the B-cell lineage and for orchestrating the Ig recombination machinery. After rearrangement of the immunoglobulin heavy chain, proliferation and apoptosis, and thus selection, are mediated by the clonal pre-B-cell receptor, and, following light chain rearrangement, by the B-cell receptor.

Pax5 determines B- versus T-cell fate and does not block early myeloid-lineage development

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4342-4346 ◽  
Author(s):  
Claudiu V. Cotta ◽  
Zheng Zhang ◽  
Hyung-Gyoon Kim ◽  
Christopher A. Klug
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Nk Cell ◽  
Cell Lineage ◽  
Blood Analysis ◽  
Hematopoietic Stem ◽  
Peripheral Blood Analysis

Abstract Progenitor B cells deficient in Pax5 are developmentally multipotent, suggesting that Pax5 is necessary to maintain commitment to the B-cell lineage. Commitment may be mediated, in part, by Pax5 repression of myeloid-specific genes. To determine whether Pax5 expression in multipotential cells is sufficient to restrict development to the B-cell lineage in vivo, we enforced expression of Pax5 in hematopoietic stem cells using a retroviral vector. Peripheral blood analysis of all animals reconstituted with Pax5-expressing cells indicated that more than 90% of Pax5-expressing cells were B220+ mature B cells that were not malignant. Further analysis showed that Pax5 completely blocked T-lineage development in the thymus but did not inhibit myelopoiesis or natural killer (NK) cell development in bone marrow. These results implicate Pax5 as a critical regulator of B- versus T-cell developmental fate and suggest that Pax5 may promote commitment to the B-cell lineage by mechanisms that are independent of myeloid gene repression.

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