RePLASTIC · Uncovering the Regulators of Cellular Plasticity by Direct Reprogramming

Uncovering the Regulators of Cellular Plasticity by Direct Reprogramming

Developmental specification is characterized by the transition of sequential cell identities that display different degrees of plasticity, ultimately leading to the generation of the numerous different cell types found in an organism. This process starts with a highly plastic cell that drops its plasticity capacity as it commits and acquires a certain cell identity, transitioning through progenitors until differentiated somatic cells. The key determinants that rule cell specification are the transcription factors, which are assisted by chromatin regulators and RNA modifiers that help to keep cell identity. In alternative to the developmental pathways, the attainment of another somatic cell type identity can also be achieved by cell reprogramming, evidencing how highly plastic cells can be. Additionally, cancer cells also exhibit remarkable plasticity, allowing them to switch lineages, develop stem-like properties, drive invasiveness, and resist treatments. Yet the principles governing plasticity in processes like development, reprogramming, and cancer cells remain poorly understood. Altogether, the key interrogations are how cellular identities are committed to a particular cell type, what defines a cell type distinguishable from other cells, and how degrees of plasticity can account for such differences. The emergence of technologies like direct reprogramming approaches, deep sequencing, and gene editing convey an excellent time in science to tackle these questions. Focused on developing an innovative strategy, the general aim of this project is to use an integrative approach to uncover molecular drivers of degrees of cellular plasticity that allow or restrict interconversion between cellular identities. To achieve this, I will take advantage of the unique reprogramming systems developed and used in the host laboratory to induce unipotent dendritic cells type 1 (iDC1), multipotent hematopoietic stem and progenitor cells (iHSPC), and pluripotent stem cells (iPSC) from human dermal fibroblasts (HDF) coupled with CRISPR/Cas9 knock-out (KO) screens targeting chromatin and RNA modifiers. This methodology will be employed to induce genetic perturbation and identify critical regulators that impact the reprogramming outcomes, therefore critical for cellular plasticity. With an interdisciplinary approach taking a leaf from the fields of gene editing, stem cells and immunology, this work will allow us to address for the first time how different degrees of plasticity are established de novo. By investigating the facilitators or barriers of plasticity at the overlap of the three cellular conversions I will identify 1) players implicated in cell state interconversion and “universal” plasticity, 2) molecular drivers conferring the potential to generate additional cell types (increased plasticity), 3) genes controlling entry to the hematopoietic lineage and 4) genes in the unipotency-pluripotency transition that could contribute to interesting revelations about this two states of plasticity. These findings will collectively reveal a world of possibilities for interrogating the complex interplay of TFs, chromatin remodelers and RNA modifiers on the basic principles of cellular identity and degrees of plasticity, relevant knowledge for several biological processes like cell reprogramming, cancer, regeneration and development.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз