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Functional collaboration between HLH transcription factors in B cell development.

Gisler, Ramiro LU (2002)
Abstract
The cells in B cell development can be divided into several subgroups or fractions, e.g. early-pro-B-, pro-B, large-pre-B-, small-pre-B-, immature and mature B cells, where the stages reflect the maturity degree of the cells. This characterization is based on the expression of intracellular markers such as the recombination activating genes 1 and 2(Rag 1 and Rag 2), the terminal deoxynucleotidyl transferase gene (TdT) and the expression of surface markers such as the components of the pre-B and B cell receptor (pre-BCR and BCR) as well as the rearrangement status of the heavy- and light chain genes. The expression of these genes is strongly regulated and controlled, otherwise it will lead to disruptions in the B cell development. One... (More)
The cells in B cell development can be divided into several subgroups or fractions, e.g. early-pro-B-, pro-B, large-pre-B-, small-pre-B-, immature and mature B cells, where the stages reflect the maturity degree of the cells. This characterization is based on the expression of intracellular markers such as the recombination activating genes 1 and 2(Rag 1 and Rag 2), the terminal deoxynucleotidyl transferase gene (TdT) and the expression of surface markers such as the components of the pre-B and B cell receptor (pre-BCR and BCR) as well as the rearrangement status of the heavy- and light chain genes. The expression of these genes is strongly regulated and controlled, otherwise it will lead to disruptions in the B cell development. One important way of maintaining this is by the interaction of proteins denoted transcription factors (TFs) and the genes regulatory sequences, i.e. promoter and enhancer sequences. This interaction, where the TFs help to stabilize and activate the transcriptional machinery, is called transcriptional regulation. Several TFs have been shown to play a crucial role in this regulation process during B cell development, since disruption of genes encoding these TFs causes developmental blocks and disruptions. Two of these factors are the Early B cell Factor (EBF) and E47. Using the mouse EBF cDNA as a probe, we managed to clone the human homologue in a human pre-B cell cDNA library. This made possible a study of the role of this protein during the human B cell development. In this thesis we suggest that EBF and E47 have conserved target sequences and function between man and mouse. This evolutionary conservation reflects their importance during B cell development. Furthermore, there is an interaction during transcription between the two TFs that in many cases result in a synergistic cooperation, reflected in the activation degree of the gene in question. Several target genes are components of the pre-BCR and positioned in different chromosomes, suggesting that EBF is a pleiotropic activator of genes encoding the pre-BCR. Also, we were able to clone a promoter region upstream the EBF gene. This sequence contain binding sites for both E47 and EBF, suggesting that E47 is a key regulator in the transcription of EBF and that EBF auto-regulates it self in a loop. This also suggests that E47 is placed upstream of EBF in the hierarchy of transcriptional factors that participates in the transcriptional regulation of B cell development. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Alla friska människor har 46 kromosomer, 23 av dessa härstammar från modern och 23 från fadern. Kromosomer är långa kedjor av nukleinsyror som innehåller den genetiska informationen (arvsanlagen) som behövs för att ett befruktat ägg skall kunna utvecklas till en individ bestående av miljontals celler med mycket specialiserade och avancerade uppgifter. Den här utvecklingen från ett befruktad ägg till en flercellig individ sker genom processer som kallas för celldelning och celldifferentiering. Samtliga celler i kroppen, med undantag för könscellerna som innehåller 23 kromosomer, innehåller exakt lika mycket genetisk information, 46 kromosomer innehållande ca 35000 gener.



En gen... (More)
Popular Abstract in Swedish

Alla friska människor har 46 kromosomer, 23 av dessa härstammar från modern och 23 från fadern. Kromosomer är långa kedjor av nukleinsyror som innehåller den genetiska informationen (arvsanlagen) som behövs för att ett befruktat ägg skall kunna utvecklas till en individ bestående av miljontals celler med mycket specialiserade och avancerade uppgifter. Den här utvecklingen från ett befruktad ägg till en flercellig individ sker genom processer som kallas för celldelning och celldifferentiering. Samtliga celler i kroppen, med undantag för könscellerna som innehåller 23 kromosomer, innehåller exakt lika mycket genetisk information, 46 kromosomer innehållande ca 35000 gener.



En gen kan beskrivas som en väldefinierad enhet av nukleinsyror som innehåller informationen för att tillverka ett protein. Proteiner är kedjor av aminosyror och har olika uppgifter i cellen. Vissa proteiner deltar i kemiska nedbrytningsreaktioner och kallas då för enzymer, andra deltar i uppbyggandet av cellmembran osv. Alla celler uttrycker inte alla 35000 gener samtidigt. Detta utgör grunden för den cellspecialisering som leder till de olika vävnadstyper som bildar organ. Det som skiljer en hudcell från en cell i en annan vävnad, t. ex. i ögat, är den exakta genuppsättning som de uttrycker, d.v.s. vilken typ av protein cellen producerar och använder sig av.



Eftersom genuttrycket är mycket betydelsefull för den enskilda cellen och för individen, är denna process utsatt för en mycket ”sträng” och stark kontroll. Det finns flera olika sätt att upprätthålla denna kontroll men den viktigaste är en mekanism som kallas för transkriptionsreglering. Transkriptionsreglering kan beskrivas som ett samspel mellan DNA, eller nukleinsyra, som finns nära en gens början och proteiner som kallas transkriptionsfaktorer. Transkriptionsfaktorerna uttrycks under bestämda tidsintervaller under cellens livscykel. När dessa transkriptionsfaktorer binder till genen startas en process som heter transkription. Detta samspel möjliggör att ett översättnings-maskineri sätts igång. Den här översättningen från deoxynukleinsyra (DNA) till ribonukleinsyra (mRNA) erfordras för att proteinet skall kunna tillverkas i en process som heter translation.



Proteintillverkningen kan förenklas med en liknelse; ett brödrecept på kinesiska (genen) översätts (transkriberas) av en tolk (transkriptions- maskineriet) till svenska (mRNA). Detta möjliggör att svenska bagare (translationsmaskineriet), med hjälp av mjöl, vatten, salt och jäst (aminosyrorna), kan baka (translatera) brödet (proteinet).



De 46 kromosomerna kan ses som 46 bokhyllor med böcker eller gener. Alla dessa böcker har små lås och för att kunna öppna dem erfodras molekylära nycklar som kallas för transkriptionsfaktorer. För att kunna läsa böckerna/generna med recept och på så sätt kunna tillverka proteinet erfordras det att vi använder oss av rätt kombination nycklar/transkriptionsfaktorer.



Eftersom vi arbetar med B-celler är våra studier inriktade på B-cellspecifika transkriptionsfaktorer. EBF, eller Early B cell Factor, och E47 är två av dem. Genom att studera hur de fungerar och vilka böcker/gener de påverkar kan vi få en djupare förståelse av genreglering och genuttryck under B-cellsutvecklingen. Denna kunskap är inte enbart tillämpbar inom immunologin utan kan också användas som modell inom genregleringen av alla vävnadstyper. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Kadesch, Tom, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
E47, Early B cell Factor (EBF), Clinical genetics, Klinisk genetik, HLH proteins, transcription factors, gene expression, B cell development, transcription regulation
pages
126 pages
publisher
Ramiro Gisler, Stem cell laboratory, BMC, B12, Klinikg.26, 22184 Lund, Sweden,
defense location
GK-salen, BMC, Lund
defense date
2002-12-06 10:15:00
ISBN
91-628-5487-9
language
English
LU publication?
yes
additional info
Article: I. Gisler R, Åkerblad P, Sigvardsson M.A human early B-cell factor-like proteinparticipates in the regulation of the humanCD19 promoter.Mol Immunol1999Oct-Nov;36(15-16):1067-77. Article: II. Gisler R, Jacobsen SE, Sigvardsson M.Cloning of human early B-cell factor andidentification of target genes suggest aconserved role in B-cell development inman and mouse.Blood 2000 Aug 15;96(4):1457-64. Article: III. Gisler R, Sigvardsson M. The humanV-preB promoter is a target for coordinatedactivation by early B cell factor and E47.J Immunol 2002 May 15;168(10):5130-8 Article: IV. Smith EM, Gisler R, Sigvardsson M.Cloning and characterization of a promoterflanking the early B cell factor (EBF) geneindicates roles for E-proteins andautoregulation in the control of EBFexpression.J Immunol 2002 Jul 1;169(1):261-70 The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Hematopoietic Stem Cell Laboratory (013022012)
id
9068833a-60cb-4e3a-b759-2d6709959254 (old id 465194)
date added to LUP
2016-04-04 10:13:25
date last changed
2018-11-21 20:57:31
@phdthesis{9068833a-60cb-4e3a-b759-2d6709959254,
  abstract     = {{The cells in B cell development can be divided into several subgroups or fractions, e.g. early-pro-B-, pro-B, large-pre-B-, small-pre-B-, immature and mature B cells, where the stages reflect the maturity degree of the cells. This characterization is based on the expression of intracellular markers such as the recombination activating genes 1 and 2(Rag 1 and Rag 2), the terminal deoxynucleotidyl transferase gene (TdT) and the expression of surface markers such as the components of the pre-B and B cell receptor (pre-BCR and BCR) as well as the rearrangement status of the heavy- and light chain genes. The expression of these genes is strongly regulated and controlled, otherwise it will lead to disruptions in the B cell development. One important way of maintaining this is by the interaction of proteins denoted transcription factors (TFs) and the genes regulatory sequences, i.e. promoter and enhancer sequences. This interaction, where the TFs help to stabilize and activate the transcriptional machinery, is called transcriptional regulation. Several TFs have been shown to play a crucial role in this regulation process during B cell development, since disruption of genes encoding these TFs causes developmental blocks and disruptions. Two of these factors are the Early B cell Factor (EBF) and E47. Using the mouse EBF cDNA as a probe, we managed to clone the human homologue in a human pre-B cell cDNA library. This made possible a study of the role of this protein during the human B cell development. In this thesis we suggest that EBF and E47 have conserved target sequences and function between man and mouse. This evolutionary conservation reflects their importance during B cell development. Furthermore, there is an interaction during transcription between the two TFs that in many cases result in a synergistic cooperation, reflected in the activation degree of the gene in question. Several target genes are components of the pre-BCR and positioned in different chromosomes, suggesting that EBF is a pleiotropic activator of genes encoding the pre-BCR. Also, we were able to clone a promoter region upstream the EBF gene. This sequence contain binding sites for both E47 and EBF, suggesting that E47 is a key regulator in the transcription of EBF and that EBF auto-regulates it self in a loop. This also suggests that E47 is placed upstream of EBF in the hierarchy of transcriptional factors that participates in the transcriptional regulation of B cell development.}},
  author       = {{Gisler, Ramiro}},
  isbn         = {{91-628-5487-9}},
  keywords     = {{E47; Early B cell Factor (EBF); Clinical genetics; Klinisk genetik; HLH proteins; transcription factors; gene expression; B cell development; transcription regulation}},
  language     = {{eng}},
  publisher    = {{Ramiro Gisler, Stem cell laboratory, BMC, B12, Klinikg.26, 22184 Lund, Sweden,}},
  school       = {{Lund University}},
  title        = {{Functional collaboration between HLH transcription factors in B cell development.}},
  year         = {{2002}},
}