Nucleus Mechanosensitivity and the Nuclear Lamina:

The nucleus is an elastic inclusion caged by the cytoskeleton and surrounded by a thin envelope that is composed of various nuclear lamins. Depending on external molecular or physical signals, the nucleus is subjected to pulling and stretching forces. The induced deformations can unfold structural nuclear proteins, alter the interactions between proteins, and perturb the nuclear matrix of lamins and chromatin. As a result, mechanical stimuli act as physical regulators of gene expression. We design cellular systems that allow us to ‘engineer’ the molecular composition of the nuclear envelope. The overall goal is to elucidate physical/molecular mechanisms that allow cells to ‘feel’ their physical surroundings and respond by specifying distinctive patterns of gene expression.

Cell differentiation and somatic cell reprogramming:

Pluripotency is maintained during the first few days of pre-implantation embryogenic development within the inner-mass of epithelial-like cells, which is a soft microenvironment where cells adhere to each other. Mesodermal differentiation involves a transition towards a stiffer surroundings that consists eventually of an extracellular matrix that cells adhere to and become contractile. We study the early differentiation of pluripotent cells and the reverse process of de-differentiation as induced by the ectopic expression of pluripotency factors. We are interested in understanding the relationship between these cell-fate decision making processes and the dimensionality and mechanics of the surrounding environment. We focus on how the emerging physical inputs propagate into the nuclear matrix of lamins and chromatin, change its composition and structure to regulate gene expression programs.

Pre-Implantation Embryogenic Development:

The first several days of embryogenic development are maintained while encapsulated inside a mechanically-firm shell, called the zona pellucida (ZP). The ZP not only prevents the embryo from early implantation at the oviduct wall, it also separates the embryo from the external environment of soluble signaling factors as well as shielding it from external physical stresses involved in tubal transport. In essence, the ZP forms an insulated micro-cosmos where the early stages of embryo development can be tightly regulated. As part of pre-implantation development, a series of distinctive physical events are temporally synchronized with major cellular phenotypic changes: morula compaction, blastocoel cavitation and blastocyst (pulsatile) expansion. We study the regulatory roles that such physical stimuli may play in directing pre-implantation development and link it to embryogenic developmental competence. We develop algorithms for image processing analysis of human pre-implantation embryogenesis and combine it with bovine experimental model system that we study in a dish.

Myotonic Dystrophy Type-1:

Myotonic dystrophy type-1 (DM1) is the most prevalent form of muscular dystrophy in adults, affecting 1 in 8000 individuals worldwide. It is characterized by a progressive muscle wasting, clinical myotonia, cardiac conduction defects and a broad multisystem involvement. DM1 is a genetically-inherited autosomal dominant disorder, caused by the expansion of a CTG trinucleotide repeat located within the 3’-untranslated region (3’-UTR) of the Distrophia Myotonica Protein Kinase (DMPK) gene and the downstream SIX5 gene promoter. DM1 involves the accumulation of ribonucleic foci comprised of long CUG repeat-containing toxic transcripts that can sequester various RNA-binding factors and lead to the misregulation of gene expression and alternative splicing. In addition, DMPK is a nuclear-envelope protein that interacts with A-type lamins whose mutated forms are widely implicated with various muscular dystrophies. We study the interactions between lamin-A,C and DMPK in muscle cells differentiated from primary human ES cell lines that were derived from DM1 embryos. The overall goal is to explore the indirect effects that DMPK mutations may induce on DM1 pathology by destabilizing the nuclear lamina. We wish to gain insights into whether DM1-induced defects in the composition and structural organization of the nuclear envelope play an important role in the progression of DM1 pathophysiology.

Positions available

Now recruiting Excellent students and postdocs who wish join an interdisciplinary research group with strong backgrounds in Life Sciences, Physics and Engineering. We look for team players who can appreciate the bigger picture.



03-march-2014 lab inauguration party

01-feb-2014 Human Embryo Team is ON!