Department of Human Genetics
Committee on Genetics, Genomics & Systems Biology
Committee on Evolutionary Biology
Committee on Cancer Biology
Committee on Neurobiology
Ph.D. Massachusetts Institute of Technology
Phone: (773) 834-4065 (lab)
Phone: (773) 834-9921 (lab)
Fax: (773) 702-0271
Our lab studies the mechanism of cell fate restriction. The approaches we take fall at the interface of several disciplines, including developmental biology, stem cell biology and epigenetics. Below is a brief summary of our work.
The hallmark of multicellular life is the presence of diverse cell types within a single organism, all bearing the same genome but disparate gene expression patterns. In mammals, as in many other taxa, this is accomplished via the progressive differentiation of pluripotent stem cells into a variety of specialized cell types. During this process, cells lose their potential for all but the lineage to which they have become committed. A longstanding but unresolved question in biology is: how is cell fate restricted during somatic differentiation? Furthermore, how is this restriction reversed during reproduction to reestablish pluripotency at the onset of development? Based on emerging data from the literature and our lab, we developed a conceptually simple model, dubbed the “gene occlusion” model, to account for cell fate restriction during somatic development and its reversal during reproduction.
The model makes three assertions: (1) A gene’s transcriptional potential can assume either the competent state wherein the gene is responsive to, and can be activated by, trans-acting factors in the cellular milieu, or the occluded state wherein the gene is blocked by cis-acting, chromatin-based mechanisms from responding to trans factors such that it remains silent irrespective of the presence of transcriptional activators. (2) As somatic differentiation proceeds, lineage-inappropriate genes shift progressively and irreversibly from competent to occluded state, thus restricting cell fate. (3) During reproduction, global deocclusion occurs in the germline and/or early zygotic cells to reset the genome to the competent state.
Monoallelic silencing such as X inactivation and imprinting is a clear example of occlusion. Here, the inactive state of the silent alleles can be causally attributed to cis (as opposed to trans) mechanisms given the presence of corresponding active alleles within the same trans environment of the cell. It was unclear, however, whether there are also many genes for which both alleles are occluded. We showed this to be the case using a cell fusion assay. Specifically, we fused two cell types and searched for genes with silent copies in one fusion partner but active copies in the other partner. The active copies served as a positive control for the presence of a transcriptionally supportive milieu, much like the active alleles of monoallelically silenced genes. With this control, the silent copies are identified as being occluded.
In the last few years, our lab has accumulated a substantial body of evidence supporting key predictions of the gene occlusion model in mammalian systems. We showed that occlusion is a prevalent phenomenon affecting a large number of genes in a variety of somatic cell types, including both terminally differentiated cells and somatic stem cells. We found that occluded genes in a given cell type include many master regulators of alternative lineages. We established a mechanistic link between DNA methylation and the maintenance of occlusion for at least some occluded genes, and showed that a variety of well-studied chromatin marks are likely not involved in occlusion. We uncovered functional evidence for a critical requirement of occlusion in cell fate restriction. Finally, we showed that embryonic stem cells are fundamentally distinct from somatic cells in that they have the capacity for genome-wide deocclusion. Collectively, these data establish the gene occlusion model as a simple and coherent conceptual framework for studying how the restriction of cell fate is brought about during development, erased during reproduction, and possibly subverted in disease.
Currently, we are continuing to study several aspects of the gene occlusion model. First, we are investigating the biochemical mechanism underlying the maintenance of occlusion in somatic cells. Second, we are probing the mechanism by which de novo occlusion is established during differentiation. Third, we are exploring the implications of gene occlusion in a variety of biological processes including stem cell differentiation, induction of iPS cells, cancer and aging.
Embryonic stem cells induce pluripotency in somatic cell fusion through biphasic reprogramming.
(Apr 2012) Molecular cell 46(2):159-70 PMID:22445485
Evidence for a critical role of gene occlusion in cell fate restriction.
The "occlusis" model of cell fate restriction.
(Jan 2011) BioEssays : news and reviews in molecular, cellular and developmental biology 33(1):13-20 PMID:20954221
Nestin is required for the proper self-renewal of neural stem cells.
(Dec 2010) Stem cells (Dayton, Ohio) 28(12):2162-71 PMID:20963821
Chromatin analysis of occluded genes.
Systematic identification of cis-silenced genes by trans complementation.
Genetic basis of human brain evolution.
Critical role of phosphoinositide 3-kinase cascade in adipogenesis of human mesenchymal stem cells.
(Mar 2008) Molecular and cellular biochemistry 310(1-2):11-8 PMID:18060476
Extensive contribution of embryonic stem cells to the development of an evolutionarily divergent host.
(Jan 2008) Human molecular genetics 17(1):27-37 PMID:17913699
Proteomic identification of differently expressed proteins responsible for osteoblast differentiation from human mesenchymal stem cells.
(Oct 2007) Molecular and cellular biochemistry 304(1-2):167-79 PMID:17530189
Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage.
Trak1 mutation disrupts GABA(A) receptor homeostasis in hypertonic mice.
(Feb 2006) Nature genetics 38(2):245-50 PMID:16380713
Robust signals of coevolution of interacting residues in mammalian proteomes identified by phylogeny-aided structural analysis.
(Dec 2005) Nature genetics 37(12):1367-71 PMID:16282975
Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.
(Sep 2005) Science (New York, N.Y.) 309(5741):1717-20 PMID:16151009
Rate of molecular evolution of the seminal protein gene SEMG2 correlates with levels of female promiscuity.
(Dec 2004) Nature genetics 36(12):1326-9 PMID:15531881
Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size.
(Jun 2004) Human molecular genetics 13(11):1139-45 PMID:15056607
Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans.
(Mar 2004) Human molecular genetics 13(5):489-94 PMID:14722158