Deciphering the regulatory network controlling blood cells specification and reprogramming

Informations générales
Détails de la thèse/HDR
Résumé en anglais
Immune cells arise from a common set of hematopoietic stem cells, which differentiate hierarchically into the myeloid and lymphoid lineages. This process is tightly regulated by an intertwined network of transcription and epigenetic factors, which control both the activation and repression of gene programs, to ensure cell commitment.
However, recent work on cellular reprogramming has shown that the ectopic expression of some specific factors can enforce the trans-differentiation of committed cells. The transcription factor C/EBPa can induce the reprogramming of B-cells into macrophages. Furthermore, a pulse of Cebpa expression in B cells followed by the expression of the four transcription factors Oct4-Sox2-Klf4-cMyc leads to an extremely fast and efficient reprogramming into induced pluripotent stem cells.
Despite the many data we have on the molecular mechanisms by which specific genes are regulated, we are still lacking a global understanding of the interplay between these factors and how they control cell fate.
In order to decipher the molecular regulatory network controlling immune cell specification and their reprogramming, I have combined a variety of high-throughput methods to measure changes in gene expression and epigenetic regulation during B cells reprogramming.
I have revealed the interplay between different transcription factors at enhancers regulating genes of the different programs (B cells, macrophages and pluripotent cells) and identified epigenetic regulators forming complexes and controlling enhancers activities (such as Lsd1, Hdac1, Brd4 and Tet2) and consequently regulating cell fate.
Finally, I integrated these data together with published data, in a computational model of the regulatory network controlling the specification of B-cells and macrophages from multipotent progenitors. I used both analytic tools (stable states analysis) and simulations (logical asynchronous simulations, continuous time Markov chains) to study in silico differentiation and reprogramming.
These analyses have revealed previously unknown transcriptional regulations, which we confirmed experimentally, and allowed us to get a better understanding of the regulatory circuits controlling cell fate commitment.