Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Staber, P.
Regulation of PU.1 in normal blood development and core binding factor leukemia: Role of chromatin structure and antisense transcription
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Medical University of Graz; 2014. pp. 115
[OPEN ACCESS]
FullText
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Gürtl-Lackner Barbara
- Höfler Gerald
- Neumeister Peter
- Altmetrics:
- Abstract:
- Blood development is regulated by levels of transcription factor PU.1 (encoded as SPI1/Sfpi1). During myeloid differentiation PU.1 levels need to increase to avoid a differentiation block, which would lead to leukemia. In contrast PU.1 expression needs to stop completely to develop T-cells. So far the mechanisms of PU.1 suppression, physiologic as for T-cell differentiation or pathologic as for leukemia development are unknown. Here we demonstrate how binding of selected transcription factors (Runx and PU.1) change the chromatin structure of PU.1 with fundamental impact on the function of normal hematopoietic stem cells (HSC) and leukemic stem cells (LSC). We found that PU.1 is a master regulator of cell cycle genes in stem cells and that a decrease of PU.1 levels results in excessive HSC proliferation and consecutively to HSC exhaustion. We further show that expression of a long noncoding antisense RNA plays a central role in silencing the expression of PU.1. We provide evidence that specific 3-dimensional chromosome architectures facilitate expression of either PU.1 mRNA or PU.1 antisense transcription by locating distal enhancer- or modifier- segments either to the proximal or the antisense promoter. Our data suggest that the tight interplay between Runx factors and PU.1 directly influences PU.1 antisense expression. Runx function is frequently affected in various leukemias such as the core-binding factor (CBF) leukemias t(8;21) and inv(16) and, importantly, PU.1 is functionally deficient in these diseases. We thus conclude that fusion oncoproteins of CBF leukemias hijack a mechanism, which is required for normal T-cell development. They establish a specific higher-order chromatin structure leading to PU.1 antisense transcription and active PU.1 silencing. Former studies have mainly focused on mechanism how transcription factors are up-regulated and regulation of PU.1 is particularly well studied in this respect. Here, we also studied the opposite suggesting that silencing transcription factor PU.1 is an active process that requires a specific chromosome formation and transcription of a non-coding antisense transcript.