We study gene regulation in adult stem cells and developing lymphocytes. Both global and single cell strategies are being utilized with the aim to describe normal development as well as aged and diseased states in molecular terms.
We have a long-standing interest in deciphering the role and regulation of helix-loop-helix proteins in lymphocyte development. This class of factors plays key roles in hematopoiesis. Currently our main interests are in the role of these factors in the control of hematopoietic stem cell homeostasis, B- and T-lineage specification and commitment, aging, inflammatory disease and their roles in the periphery in the response to invading pathogens.
Recent genome-wide studies have identified that a large fraction of the genome transcribed in non-coding regions. We are now faced with the question as to how these large non-coding RNAs relate to the control of gene expression. We have identified a subset of lineage-specific and developmental-stage specific non-coding RNAs. Our interests are to determine the function of these non-coding RNAs and to study their potential roles in modulating long-range chromatin structure and genomic interactions.
Our knowledge of chromatin structure and long-range genomic interactions in mammalian cells is still rudimentary. How do the genomes of lymphocytes, plasma cells and granulocytes adopt such unique and distinct structures? We aim to resolve these questions using genome-wide chromosome-conformation capture studies (HiC) in conjunction with computational approaches to describe the topologies of lymphoid and myeloid genomes in molecular terms.
During developmental progression of lymphoid cells coding and regulatory elements interact to induce lineage-specific programs of gene expression. We recently found that in eukaryotic cells coding and regulatory genomic elements bounce back and forth within the chromatin network until specific genomic interactions are established, and that spatial confinement of topological domains largely controls the times for such encounters. Our future studies aim to examine how epigenetic and structural determinants affect the trajectories adopted by the chromatin fiber in living cells and how this relates to genomic encounters involving enhancers and promoters.
We have recently demonstrated that genes encoding for key developmental regulators reposition during developmental progression. We now aim to address the question as to why and how genomic regions encoding for developmental regulator reposition during developmental progression, how their release from the lamina is regulated and how they associate with active transcription factories.
Kees Murre performed his graduate work at Harvard Medical School and was a postdoctoral fellow at MIT. He is a Searle Scholar and the recipient of the National Institutes of Health Merit Award.