Objective
Hematopoiesis is an important model for stem cell differentiation with great medical significance.
Heterogeneity within hematopoietic progenitor populations has considerably limited characterization and
molecular understanding of lineage commitment in both health and disease. Advances in single-cell genomic
technologies provide an extraordinary opportunity for unbiased and high resolution mapping of biological
function and regulation. Recently we have developed an experimental and analytical method, termed
massively parallel single-cell RNA-Seq (MARS-Seq), for unbiased classification of individual cells from
their native context and successfully applied it for characterization of immune and hematopoietic
progenitors.
Here, we propose to uncover the hierarchy and regulatory mechanisms controlling hematopoiesis by
combining comprehensive single-cell RNA-Seq analyses, modelling approaches, advanced functional assays,
single-cell CRISPR screens, knockout models and epigenetic profiling. Exciting preliminary result show that
indeed our approach is starting to uncover the complexity of hematopoietic progenitors and the regulatory
circuits driving hematopoietic decisions. We will pursue the following aims: (i) Generate a refined model of
hematopoiesis by comprehensive single-cell RNA-Seq profiling of hematopoietic progenitors, (ii) validate
the predicted model by in vivo functional developmental assays and then (iii) test candidate transcription and
chromatin factors uncovered by our model for their role in controlling progression towards various lineages
using single-cell measurements combined with CRISPR screens. Together, our study is expected to generate
a revised and high-resolution hematopoietic model and decipher the regulatory networks that control
hematopoiesis. Our methods and models may provide a platform for future medical advancements including
a large-scale European collaborative project to discover a comprehensive human hematopoietic tree.
Fields of science
Keywords
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
7610001 Rehovot
Israel