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Analysis of class I histone deacetylases in B cell development and antibody diversification

English title Analysis of class I histone deacetylases in B cell development and antibody diversification
Applicant Matthias Patrick
Number 173274
Funding scheme Project funding (Div. I-III)
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Embryology, Developmental Biology
Start/End 01.10.2017 - 30.09.2021
Approved amount 568'857.00
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All Disciplines (4)

Discipline
Embryology, Developmental Biology
Genetics
Molecular Biology
Immunology, Immunopathology

Keywords (8)

Antibody diversification; VDJ recombination; B cells; Histone deacetylases HDAC; Chromatin; Acetylation; Cancer and tumorigenesis; Epigenetics

Lay Summary (German)

Lead
Dieses Projekt untersucht Enzyme, die „Chromatin Modifikationen“ regulieren. Diese Enzyme -Histon Deacetylasen (HDACs) genannt- entfernen eine bestimmte Modifikation (Acetylation) und haben dabei einen Einfluss auf die Expression von Genen. HDACs sind oft dereguliert in Krebs und werden deshalb als ein Target für die Krebstherapie betrachtet. Aus diesen Gründen wurden Inhibitoren von HDACs (HDACis) in den letzten Jahren entwickelt: inzwischen sind vier solche Inhibitoren für Krebsbehandlung zugelassen. Die Rolle von HDACs in der normalen Zell- und Organismus-Physiologie ist jedoch noch ungenügend verstanden. Das Projekt wird auf diesem Gebiet einen Beitrag leisten.
Lay summary

Inhalt und Ziele des Forschungsprojekts: Das Projekt wird die Rolle von verschiedenen HDACs, insbesondere HDAC1, 2 und 3, in Blutzellen näher untersuchen. Das Ziel ist besser zu verstehen, welche Rolle diese Enzyme für die Bildung von einer Kategorie von weissen Blutzellen (die B-Zellen) spielen. Dabei möchte man verstehen, welche Differenzierungsprozesse von diesen Enzymen beinflusst sind. B-Zellen sind sehr wichtig für die Immunantwort und sind für die Antikörper Produktion verantwortlich. Im Rahmen des Projekts, wird man untersuchen, welche Rolle diese HDACs für die Antikörper Produktion haben, und welche molekulare Mechanismen involviert sind. Ein anderes Ziel ist zu sehen, ob HDAC1, 2 und 3, allenfalls eine Rolle in der Enstehung von B-Zell Tumoren spielen könnten.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts: Dieses Projekt wird zu einem besseren Verständnis der Function von Histon Deacetylasen in B-Zellen in ihrem normalen und aktivierten Zustand beitragen. Neue Erkenntnisse werden nicht nur für die Grundlagenforschung, sondern auch möglicherweise für die biomedizinische Forschung, insbesondere für immunbezogenen Erkrankungen, von Bedeutung sein. Ein Aspekt vom Projekt wird auch Relevanz für die Krebsforschung haben.

Direct link to Lay Summary Last update: 27.09.2017

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Abstract

B cell development is driven by the interplay of transcription factors and epigenetic regulators. Histone acetylation is an epigenetic mark crucial for DNA accessibility of transcription factors, but also of factors that control V(D)J recombination, class switch recombination (CSR) and somatic hypermutation (SHM), processes that are the basis for antibody diversification in B cells. Previous studies revealed that timely acetylation of specific regions in the immunoglobulin (Ig) locus is crucial for proper orchestration of these processes. However, knowledge about epigenetic modifiers controlling acetylation during these processes is largely missing. We hypothesize that Class I histone deacetylases (HDACs), which are key in controlling chromatin acetylation, play crucial roles in proper regulation of these processes. Moreover, we hypothesize that deregulation of Class I HDACs leads to aberrant targeting of these processes, which in turn might lead to lymphomagenesis. The latter hypothesis is of particular interest, as Class I HDACs are targeted in cancer patients by several HDAC inhibitors. In addition, ongoing preclinical studies suggest that these drugs have potential application in other pathologies, such as inflammation, or neurodegenerative- and psychiatric diseases. In light of these clinical applications of HDAC inhibitors, it is of paramount importance to understand how specific HDACs contribute to normal biological processes, such as for example B cell development and antibody diversification. To investigate our hypotheses, we propose here an in depth study investigating the role of Class I HDACs in B cell development and antibody diversification processes. Our aim is to first perform phenotypical analysis, focussing on B cell development, V(D)J recombination, CSR and SHM. To do this we will use conditional murine knockout models in which we ablate Class I histone deacetylases either partly or completely in B cells. Initial phenotypical studies focussing on Hdac1 and Hdac2 already revealed highly interesting observations. We found that these enzymes play a role in controlling V(D)J recombination, Ig locus contraction, and the ratio of Ig light chain kappa versus lambda expressing B cells; these processes are dependent on the dosage of Hdac1 and Hdac2. Moreover, we found that these enzymes regulate the expression of hematopoietic stem cell markers as these remain expressed in early B cells. Detailed description of these phenotypes and potential new phenotypes will be accompanied by mechanistic studies, to understand the underlying molecular basis. This will use state of the art technology as available.Besides mechanistic studies we will examine if potential phenotypes related to the highly mutagenic antibody diversification processes might create a condition in which tumorigenesis can occur. For this, we will immunize our mouse models to induce CSR and SHM and monitor tumor development over time. These and other experiments described in this proposal should generate a complete understanding about Class I HDACs in B cell development and antibody diversification processes. Finally, this information will deepen our insights on how inhibition of Class I HDACs in leukemia or myeloma patients treated with HDAC inhibitors affects normal B cell function. Moreover, it might also contribute to decision making of which HDACs to target in disease and which should be spared because of possible unwanted side-effects.
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