The research in my lab focuses on studying genetic and epigenetic factors that cause congenital craniofacial disorders, namely cleft lip and palate and Pierre Robin syndrome. In particular, my lab investigates the role of IRF6 and TWIST1 transcription factors in jaw development during pregnancy. We use mice as an animal model to understand how a tumor suppressor protein IRF6 - expressed in epithelial cells, genetically interacts with a proto-oncogenic protein TWIST1 - expressed in adjacent cranial neural crest (CNC) cells. These CNC cells are the progenitor cells that give rise to bone and cartilage of the jaw. One of the questions that we are interested in answering is why the murine embryos and pups that are double heterozygous for Irf6 and Twist1, have mandibular abnormalities, i.e. micrognathia (small mandible) and agnathia (no mandible), while the single heterozygotes do not. My lab has determined a signaling pathway that is important in epithelial-mesenchymal interaction, and acts as a candidate pathway to understand the non-cell autonomous genetic interactions between Irf6 and Twist1.
Another research area that my lab focuses on is bioinformatic analysis and modeling at the genome-wide level to understand how developmentally regulated genes are wired through feedback loops. We are interested in identifying the regulatory pathways involved in craniofacial development that will allow us to identify novel genes that cause human genetic disorders, and to develop therapeutic approaches that target protein stability or degradation.
1. Fakhouri WD, Attanasio C, Kouwenhoven EN, Rahimov F, Nitschke L, Huver D, Barrons J, deLima R, Felix TM, de Lima RF, Leslie E, van Bokhoven H, Zhou H, Murray JC, Schutte BC. 20--. A rare mutation disrupts IRF6 enhancer activity in a family with Van der Woude syndrome. In prep. PNAS.
2. Fakhouri WD, Rhea L, Du T, Sweezer E, Morrison H, Fitzpatrick D, Yang B, Dunnwald M, Schutte BC. 2012. MCS9.7 enhancer activity is highly, but not completely, associated with expression of Irf6 and p63. Dev. Dyn. 241,340-49.
3. Letra A, Fakhouri W, Fonseca RF, Menezes R, Kempa I, Prasad JL, McHenry TH, Lidral AC, Moreno L, Murray JC, Daack-Hirsch S, Marazita ML, Castilla EE, Lace B, Orioli IM, Granjeiro JM, Schutte BC, Vieira AR. 2012. Interaction between Irf6 and Tgfa genes contributes risk for nonsyndromic cleft lip/palate. PLoS One 7 (9), e45441.
4. Fakhouri WD, Ay A, Sayal R, Dresch J, Dayringer E, Arnosti DN 2010. Deciphering a transcriptional regulatory code: modeling short-range repression in the Drosophila embryos. Molecular Systems Biology EMBO Nature 6 (341), 1-14.