Dynamics and Organization of the Nucleus
The nucleus houses the genome and is therefore the central hub that controls gene expression and, ultimately, cell fate. The Department is actively engaged in exploring:
- Mechanisms that establish the 3D organization of the genome. Fitting two meters of DNA into a eukaryotic nucleus that is microns in diameter requires mechanisms to compact the DNA, which is achieved in part by its association with histones and other proteins in the form of chromatin. Understanding how the organization of chromatin can retain sufficient flexibility and dynamicity to ensure the proper and timely execution of transcriptional programs remains a central challenge. Labs in the department are exploring the underlying mechanisms that package DNA into chromatin and how this organization changes during embryonic development, through the execution of stem cell differentiation and induced pluripotent stem cell reprogramming.
- Mechanisms that control mechanical and biochemical communication between the nucleus and cytosol. The nucleus is surrounded by a double membraned nuclear envelope perforated by nuclear pores. These nuclear pores are filled with massive protein assemblies called nuclear pore complexes (NPCs) that control all molecular traffic across the nuclear envelope. Faculty in the Department are tackling the molecular mechanisms that control the biogenesis and the maintenance of the nuclear envelope membranes in the context of both physiological and pathological disruptions to the nuclear envelope barrier. In addition, extracellular mechanical environments are now established to contribute to cell fate decisions. Both biochemical and direct mechano-transduction through the linker of nucleoskeleton and cytoskeleton (LINC) complexes are being investigated as key transmitters of mechanical signals in the context of several differentiation models as well as stem cell reprogramming.
- How nuclear dysfunction causes disease. Advances in modern genomics are identifying an expanding list of human disease genes, many of which encode nuclear and nuclear envelope factors. Thus, human disease genetics is now a discovery tool for cell biologists, allowing the pursual of previously undiscovered molecular mechanisms that directly impinge on our understanding of human pathology.
- Transcriptional and translational control of embryonic development. The timely execution of gene expression programs critical for development relies on elaborate control mechanisms at the gene, transcriptional and translational levels. Laboratories in the department are at the forefront of interrogating how epigenetic modifications and non coding RNAs control cell fate decisions in the early embryo.