Research Description

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.

Selected Publications

Lee JH, Gaetz J, Bugarija B, Fernandes CJ, Snyder GE, Bush EC & Lahn BT. Chromatin analysis of occluded genes. Human Molecular Genetics. 18:2567 (2009).

Lee JH, Bugarija B, Millan EJ, Walton NM, Gaetz JFernandes CJ, Yu WH, Mekel-Bobrov N, Vallender TW, Snyder GE, Xiang AP & Lahn BT. Systematic identification of cis-silenced genes by trans complementation. Human Molecular Genetics. 18:835 (2009).

Vallender EJ, Mekel-Bobrov N & Lahn BT. Genetic basis of human brain evolution. Trends in Neurosciences. 31:637 (2008).

Yu WH, Chen ZG, Zhang JL, Zhang LR, Ke H, Huang LH, Peng YW, Zhang XM, Li SN, Lahn BT & Xiang AP. Critical role of phosphoinositide 3-kinase cascade in adipogenesis of mesenchymal stem cells. Molecular and Cellular Biochemistry. 310:11 (2008).

Xiang AP, Mao FF, Li WQ, Park D, Ma BF, Wang T, Vallender TW, Vallender EJ, Zhang L, Lee J, Waters JA, Zhang XM, Yu XB, Li SN & Lahn BT. Extensive contribution of embryonic stem cells to the development of an evolutionarily divergent host. Human Molecular Genetics. 17:27 (2008).

Zhang AX, Yu WH, Yu XB, Ma BF, Yu XB, Mao FF, Liu W, Zhang JQ, Zhang XM, Li SN, Li MT, Lahn BT & Xiang AP. Proteomic identification of differently expressed proteins responsible for osteoblast differentiation from human mesenchymal stem cells. Molecular and Cellular Biochemistry. 304:167 (2007).

Evans PD, Mekel-Bobrov N, Vallender EJ, Hudson RR & Lahn BT. Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage. PNAS. 103:18178 (2006).

Gilbert SL, Zhang L, Forster M, Anderson JR, Iwase T, Soliven B, Donahue LR, Sweet HO, Bronson RT, Davisson MT, Wollmann RL & Lahn BT. Trak1 mutation disrupts GABA_A receptor homeostasis in hypertonic mice. Nature Genetics. 38:245 (2006).

Choi SS, Li W & Lahn BT. Robust signals of coevolution of interacting residues in mammalian proteomes identified by phylogeny-aided structural analysis. Nature Genetics. 37:1367 (2005).

Mekel-Bobrov N, Gilbert SL, Evans PD, Vallender EJ, Anderson JR, Hudson RR, Tishkoff SA & Lahn BT. Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens. Science. 309:1720 (2005).

Evans PD, Gilbert SL, Mekel-Bobrov N, Vallender EJ, Anderson JR, Tishkoff SA, Hudson RR & Lahn BT. Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans. Science. 309:1717 (2005).

Dorus S, Vallender EJ, Evans PD, Anderson JR, Gilbert SL, Mahowald M, Wyckoff GJ, Malcom CM & Lahn BT. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell. 119:1027 (2004).

Dorus S, Evans PD, Wyckoff GJ, Choi SS & Lahn BT. Rate of molecular evolution of the seminal protein gene SEMG2 correlates with levels of female promiscuity. Nature Genetics. 36:1326 (2004).

Evans PD, Anderson JR, Vallender EJ, Choi SS & Lahn BT. Reconstructing the evolutionary history of Microcephalin, a gene controlling human brain size. Human Molecular Genetics. 13:1139 (2004).

Evans PD, Anderson JR, Vallender EJ, Gilbert SL, Malcom CM, Dorus S & Lahn BT. Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans. Human Molecular Genetics. 13:489 (2004).