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Fakhouri Lab

UTHealth School of Dentistry Research Labs

Overview

Understanding the underlying mechanisms of gene interactions, uncovering druggable genes and modulation of regulatory pathways can lead to innovative treatment and preventative plans for families affected or at high risk of having a child with craniofacial birth defects.

Our lab utilizes mouse models and organ cultures to delineate the molecular mechanism of a novel genetic interaction between two transcription factors, IRF6 and TWIST1, that plays a critical role in regulating the epithelial-mesenchymal interaction during oral, facial and skull development. By applying both biochemical and genetic approaches, the lab investigates how mutations in TWIST1 phospho-sites disrupt formation of craniofacial tissues derived from mesenchymal cells. The lab also integrates experimental data and bioinformatics for developing computational models to identify etiologic non-coding DNA variants associated with cancer diseases, including head and neck squamous cell carcinoma.

The goal of our research is to translate bench findings into clinical use to improve the risk assessment, healthcare and overall well-being of families affected with craniofacial birth defects by advancing personalized medicine.

Projects

  • A Computational Model for Predicting Deleterious Non-coding DNA Variations in Cancer

    A Computational Model for Predicting Deleterious Non-coding DNA Variations in Cancer

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    Identification of causative DNA variants in common complex diseases is very important to screen individuals with high-risk for diseases and for developing therapies to target the genetic cause of diseases, in particular cancer. DNA variations that lie outside the protein-coding regions can alter gene expression without affecting its protein function. This research area is critical in the context of disease susceptibility and severity. Basic and translational research has been previously directed towards DNA variations located within sequences that code for protein products due to their obvious effect on the function of the corresponding protein. However, recent genome-wide association studies demonstrate that the majority of DNA variants associated with cancer and other common complex diseases are located in outside the protein coding-regions, while few causative regulatory variants have been identified so far. The specific function of sequences that lie outside the protein-coding regions is not known for the majority of the loci compared to those within the coding regions, which makes prediction of the effect of non-coding variants challenging.

    Funding

    R15, NIH-GH122030-01

  • A novel function of IRF6 in salivary gland development

    A novel function of IRF6 in salivary gland development

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    Xerostomia (dry mouth) is a common health problem that can cause long-lasting harm to affected individuals and substantially decreases their quality of life. Xerostomia occurs due to reduced salivary flow (hyposalivation) or changes in saliva composition as a result of damaging environmental or genetic factors that affect salivary gland (SG) function, such as autoimmune disorders. Hyposalivation is the most common complication of radiation therapy for head and neck cancer. Prevention of hyposalivation due to SG dysfunction or autoimmune disorders is currently unavailable. Therefore, there is a dire need to develop innovative therapies to prevent and treat this health issue. Human genetic studies showed that haploinsufficiency of the transcription factor Interferon Regulatory Factor 6 (IRF6) causes Van der Woude syndrome associated with chronic inflammation of minor salivary glands. Our studies showed that IRF6 is necessary for SG development. Lack of Irf6 causes disruption in branching morphogenesis and acinar differentiation. Our analyses of RNA-seq, RTqPCR, and immunostaining identified the differentially altered genes in Irf6 null SGs, involved in TGFb3 pathway and immune system. We will investigate the Irf6-dependent pathway involved in acinar cell differentiation, and elucidate the function of Irf6 in SG maturation and inflammation in adult mice. We will determine if IRF6 binds to regulatory elements of Col9a2, Hoxb6, Erg1, and Ltbp4 and whether these genes can rescue the phenotype in Irf6 null explants. We will determine the role of IRF6 in SG maturation and cytokine-mediated inflammation in tissue-specific inducible Irf6 knockout mice. The findings of this proposal will lay the groundwork for future studies to determine the importance of the IRF6 pathway in SG differentiation and inflammation.

    Funding

    R03, NIH-DE027155-01 (Pending)

    Publications

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429578/

  • Regulation of cell fate during early craniofacial development

    Regulation of cell fate during early craniofacial development

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    This project aims to accelerate the identification of pathological non-coding DNA variations to improve cancer screening and prevention. Recent genome-wide association studies have reported that the majority of DNA variations associated with cancer and common complex diseases are located in non-coding regions, yet only a few causative mutations have been identified. To fill this gap, there is a tremendous need to understand the underlying mechanisms by which regulatory DNA variations disrupt gene expression, and to develop a biology-based model that integrates the crucial parameters involved in dictating regulatory element activity. Our data of human genomic binding profiles of P53 and cMYC in cancer cells showed a significant number of co-occupied putative enhancers that contain cis-overlapping binding motifs (CisOMs) for P53 and cMYC. These findings suggest a novel mechanism of gene regulation by which the tumor suppressors, P53 and P63, and tumor inducers, cMYC and HIF-1a, compete at CisOMs to regulate target gene expression. Our goals for this project are to a) determine the impact of P53/P63 and cMYC/HIF1a competitive inhibition on enhancer activity, b) identify deleterious DNA variants within CisOMs using GEMSTAT model, and c) validate the accuracy of prediction of DNA variants in vitro and in vivo for parameter optimization.

    Funding

    R01, NIH/NIDCR (Pending)

  • IRF6 in osteonecrosis of the jaw induce by bisphosphonates

    IRF6 in osteonecrosis of the jaw induce by bisphosphonates

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    A unique approach to uncover medication-related osteonecrosis of the jaw (MRONJ) is through genetic studies. Our lab has been investigating the transcription factor, IRF6, that functions as a tumor suppressor in bone development. Our published data has shown that Irf6 is expressed in cranial osteocytes, osteoclasts, and oral epithelium (Thompson, et al., 2019). The Irf6 gene is highly expressed in oral epithelium, mucosa, and macrophages, while moderately expressed in osteocytes. Loss of Irf6 leads to craniofacial bone abnormalities, including disorganized bone structure, reduction in the number of osteoclasts, and less mineralized bone. The bone matrix in Irf6 null mice is void of osteocytes in multiple regions of the mandible. Because the phenotype of Irf6 null mice shares bone matrix and cell profile characteristics with the histopathological presentation of MRONJ, it suggests that Irf6 might play a crucial role in the genetics of MRONJ.

    Funding

    AADR-Houston Chapter, UTHealth SOD

Lab Team

Walid Fakhouri, MSc, PhD
Assistant Professor
Walid.D.Fakhouri@uth.tmc.edu
713-486-2519
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Rabia Ahmed
Research Assistant I
Rabia.Ahmed@uth.tmc.edu
713-486-2732
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Kent Healy
4th Year Dental Student
Kent.Healy@uth.tmc.edu


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Rahul Paul
1st Year Dental Student
Rahul.A.Paul@uth.tmc.edu


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David Drake
1st Year Dental Student
David.A.Drake@uth.tmc.edu


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Alina Naqvi
Pre-Baccalaureate Trainee
aan3@rice.edu


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Gianncarlo Cruz
4th Year Dental Student
Gianncarlo.Cruz@uth.tmc.edu


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Key Publications

Key Publications:

  1. Kareem A. Metwalli, Megan A. Do, Kara Nguyen, Sathi Mallick, Katherine Kin, Nadia Farokhnia, Goo Jun, Walid D Fakhouri. Interferon Regulatory Factor 6 is necessary for salivary gland and pancreas development, J Dent Res 2018, 97 (2), 226-236. (cited 9, IF 4.6) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429578/
  2. Walid D Fakhouri, Kareem Metwalli, Ali Naji, Sarah Bakheit, Angela Quispe-Salcedo, Larissa Nitschke, Youssef A Kousa, Brain C Schutte. Intercellular genetic interaction between Irf6 and Twist1 during craniofacial development. Scientific Reports, 2017, DOI:10.1038/s41598-017-06310. https://www.nature.com/articles/s41598-017-06310-z
  3. Kousa YA, Zhu H, Fakhouri WD, Lei Y, Kinoshita K, Roushangar RR, Leslie EL, Busch TD, Williams TJ, Chai Y, Amendt BA, Murray JC, Shaw GC, Bassuk AG, Ashley-Koch A, Gregory S, Finnell RH, Schutte BC. A conserved role of IRF6 in neurulation. Human Molecular Genetics, 2019, January 25, doi.org/10.1093/hmg/ ddz010. F1000Prime Recommendations https://pubmed.ncbi.nlm.nih.gov/30689861/
  4. Nishtha Joshi, Ahmad Hamdan, Walid D Fakhouri. Skeletal malocclusion; a developmental disorder with a life-long morbidity. J Clinical Medicine Research. 2014; 6(6): 399-408. PubMed PMID: 25247012. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169080/

Link to NIH publications:

https://pubmed.ncbi.nlm.nih.gov/?term=Fakhouri%20WD%5BAuthor%5D&cauthor=true&cauthor_uid=25247012

News

Featured

2021 Dean’s Excellence Award winners announced

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Eight faculty members have been named recipients of the UTHealth Houston School of Dentistry Dean’s Excellence Award for 2021 in recognition of their outstanding work in the categories of Application, Discovery, Integration, Teaching, Mentoring, and Volunteerism.

Announcements

Drs. Fakhouri and Letra Special Issue Editors invited investigators to submit their research manuscripts to the Special Issue "DNA Variations in Evolution and Human Diseases"

https://www.mdpi.com/journal/genes/special_issues/DNA_Variations_Evolution_Human_Diseases?view=compact&listby=date

 

Drs. Fakhouri, Matsumoto, Biguetti, and Soldatos invite investigators tto submit their research manuscripts to the Special Issue " Craniofacial Bone and Dental Genetics, Metabolism, Aging, and Disorders"

https://www.mdpi.com/journal/genes/special_issues/Bone_Genetics

Lab Photos

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