RESUMEN DE INVESTIGACION

We would like to understand the fundamental question of the control of cell differentiation, how a cell moves from one genetic program to another. The difference between the cells of our body is the set of genes they express. Pathological situations tend to be associated with aberrant patterns of gene expression. Gene expression starts at the DNA, which can be modified to be silent. The second control level is the kind of modification of the proteins wrapping the DNA, again rendering the gene silent or active. Third, the right protein factors must direct the transcription machinery to the site at which to start transcribing the gene. These proteins work in teams, and the relative abundance of each will drive the cell to take one path or another. Our group plans a detailed analysis of these factors at the single cell level, to understand the regulation of cell differentiation and pathology.

All cells in the organism are derived from the same progenitors through differentiation, which can be seen as a progressive change in phenotype. The phenotype of any cell is ultimately determined by the set of genes transcribed, which are determined by specific transcription factors and epigenetic modifications of chromatin in the cell nucleus.

This idea was recently challenged by the observation that genetically identical populations of cells can exhibit cell-to-cell variations in the amount of protein a gene produces, resulting in phenotypic diversity. It is thought that the variations arise from the typically small number of molecules involved in gene expression. Protein numbers are often in the order of hundreds of molecules, mRNA in the order of tens of molecules, and the genes themselves are often present in just one or two copies per cell.

We attempt to understand how the organisation of transcription in the nucleus affects haematopoietic cells during differentiation, how transcription factors and extrinsic factors modulate gene expression. These analyses will provide some essential rules to understand how gene expression is integrated in the nuclear context and how nuclear structure and cellular processes influence gene activity.

The factors leading to cell-to-cell variation can be classified as originating from two sources:

• variations in global, or extrinsic, factors, such as varying amounts of transcriptional activators, or
• essentially random, or intrinsic, molecular events, such as the transcription of a particular gene that is regulated by a specific set of activators.
  

My group studies the contribution of the different factors to cell-to-cell variation, using single-cell and genomic approaches. Our long-term goal is to build a detailed map of processes such as cell differentiation and transformation.