Dr. Brad Merrill
Ph.D., University of California, San Diego, 1999Postdoc, University of Chicago, and Rockefeller University, 2004
In the Merrill lab, we endeavor to reveal basic molecular mechanisms of how cells determine their fates, and how cell fate decisions direct embryogenesis and the maintenance of stem cells in vivo. We have focused most of our recent efforts on the earliest stages of mammalian embryogenesis, where embryonic cells possess a special property named pluripotency. Pluripotency is the ability to contribute to any and all of the different types of cells found in the adult body. For a mammalian body to develop from a single cell, early embryonic cells must first maintain pluripotency as they proliferate to form a larger mass. Then pluripotency must be extinguished to allow for the specification of cells with specific physiological characteristics.
Our research usually involves some aspect of the Wnt/β-catenin signaling pathway. For pluripotent cells, we and others have found that Wnt/β-catenin signaling is instrumental for both the maintenance of a pluripotent state and also for some of the early transitions out of pluripotency and towards a lineage specific fate. We are in the process of elucidating the mechanisms whereby Wnt/β-catenin signaling can stimulate each of these ostensibly contradictory outcomes from pluripotent cells. Part of the explanation comes from a new molecular function for Tcf7l1 (previously known as Tcf3), which is one of the DNA-binding transcriptional effectors of Wnt/β-catenin. We found that Wnt/β-catenin inhibits Tcf7l1 binding to DNA, resulting in its degradation (Shy et al, Cell Reports). This finding challenges the dogma of β-catenin converting Tcf/Lef proteins into activators and is important for understanding the effect of Wnt/β-catenin on pluripotent stem cells.
We pursue our interests with a variety of fancy new technology and reliable old school methods. Currently the lab is heavily using genome editing with CRISPR/Cas9 and developing new editing tools in conjunction with our Genome Editing core facility at UIC (https://sites.google.com/site/genomeedits/). We are also using several genome-wide techniques to assess the effects of Wnt/β-catenin on the chromatin and nuclear organization in stem cells. These new techniques are combined with mouse embryology and developmental biology to deliver what we consider new understanding of physiologically significant processes.
Shy, B.R., Wu, C.I., Khramstova, G.F., Zhang, J.Y., Olopade, O.I., Goss, K.H., Merrill, B.J. Regulation of Tcf7l1 DNA binding and protein stability as principle mechanisms of Wnt/β-catenin signaling. Cell Reports 4(1) 1-9. 2013 (Cover)
Hoffman J.A., Wu, C.I., and Merrill, B.J. Tcf7l1 prepares epiblast cells in the gastrulating mouse embryo for lineage specification. Development 140(8): 1665-75. 2013 (Image chosen for Development’s Twitter and Facebook avatar)
Wu, C.I., Hoffman, J.A., Shy, B.R., Ford, E.M., Fuchs, E., Nguyen, H., and Merrill, B.J. Function of Wnt/β-catenin in counteracting Tcf3-repression through Tcf3-β-catenin interaction. Development 139(12):2118-29. 2012 (evaluated by Faculty of 1000)
Yi, F., Pereira, L., Hoffman, J.A., Shy, B.R., Yuen, C.M., Liu, D.R., Merrill, B.J. Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal. Nat Cell Biol. 13(7):762-70. 2011 (evaluated by Faculty of 1000)