Dynamic regulation of GATA transcription factors in hematopoiesis

The hematopoietic system is composed of a variety of cells, whose activity is essential for the normal functioning of an organism. Erythrocytes, or red blood cells, transport oxygen and carbon dioxide throughout the body, platelets are essential for coagulation and white blood cells (lymphocytes, granulocytes and macrophages) are responsible for the protection of the organism against pathogens. All these different cells originate from a single cell type, the hematopoietic stem cell (HSC), through a process denominated hematopoiesis. To understand how the HSC can originate so many different cell type has been the aim of many scientists over the years. Advances in molecular biology tools allowed the gathering of vast amounts of information about the hematopoietic system and the process of hematopoiesis. However, many questions remain without answers. The HSC gives rise to the different hematopoetic cell lineages via a series of steps. HSCs are rare cells that have the capacity to duplicate themselves (self-renewal) as well as to give rise to all the different hematopoietic cell types (pluripotency). The descendants of the HSC are still able to give rise to all hematopoietic lineages but they lose the ability to self-renew. These cells will further differentiate into other cells that can give rise to an increasingly restricted number of hematopoietic lineages until they reach a stage were they can only differentiate into a single lineage. Such process is called lineage-commitment and its accuracy is essential for the normal function of the hematopoietic system. How this lineage commitment occurs is as yet not clear. It is known that it is dependent on environmental cues as well as, at least partially, on stochastic events. The identity of each cell is dependent on their particular gene expression profile. Each cell expresses certain genes that are responsible for its specific characteristics. Transcription factors, proteins able to bind DNA and regulate the transcription of particular genes, are essential for the production of such expression profiles. There are two broad types of transcription factor: general transcription factors, which are present in every cell, and lineage-specific transcription factors, present only in particular cell lineages. Lineage-specific transcription factors are the main proteins responsible for the expression of genes in specific cell lineages, and are therefore responsible for their unique gene expression profiles. A variety of transcription factors has been identified which are crucial for the different lineage-commitment steps during hematopoiesis. To generate the appropriate gene expression profiles, the function of these transcription factors must be tightly regulated. Expression of particular genes in the inappropriate cell lineage or at the wrong time may have severe consequences. Transcription factors functions, like any other protein, can be regulated at transcriptional level, controlling the expression of the protein, or after the protein is produced by modulating its activity. This thesis is focused on the importance of the transcription regulation of the GATA hematopoietic transcription factors. Three of the six members of the GATA family of transcription factors are expressed in the hematopoietic system. GATA1 is expressed in the erythroid, megakaryocytic, eosinophil and mast cell lineages. GATA2 in expressed in early multilineage precursors and in the erythroid and mast cell lineages while GATA3 is expressed exclusively in T-lymphocytes. In the studies presented in this thesis transgenic mice, were used where the expression of these genes is altered, to analyse the importance of the correct spatio-temporal regulation of these genes for the differentiation of the hematopoietic lineages were they are expressed.