Department of Genetics, Cell Biology and Anatomy
PhD, Tufts University, 2011
Post-doc, University of Wisconsin-Madison, 2018
Our research employs multidisciplinary approaches to identify gene regulatory networks and cell signaling mechanisms that control blood production during development and/or regeneration following disease or injury. We focus on transcriptional and epigenetic mechanisms that cause hematologic disorders, including cancer and anemia, and mechanisms that regulate the function of hematopoietic stem and progenitor cells. Establishing fundamental principles that govern blood homeostasis (and genetic mutations that predispose illness) is an essential step towards developing personalized medicine approaches and advancing translational strategies to treat disease.
Samd14: A GATA factor- and anemia-regulated protein that promotes survival and c-Kit signaling
As mutations in the GATA-2 transcription factor can cause diverse hematologic diseases (including myelodysplastic syndrome, acute myeloid leukemia, primary immunodeficiencies and aplastic anemia), our lab is interested in elucidating downstream targets that confer GATA-2 function. We are particularly focused on the Sterile α-Motif Domain 14 (Samd14) locus, which contains an intronic, GATA-factor regulated cis-element (Samd14-Enh). Samd14-Enh-/- mice are unable to recover from a hemolytic anemia “stress test”, suggesting that Samd14 is required for adequate regeneration of red blood cells. However, Samd14 remains poorly studied and major knowledge gaps remain. Samd14-Enh stimulates SCF/c-Kit signaling, which is an important signaling pathway in blood regeneration, stem cell transplantation, hematopoietic/erythropoietic progenitor expansion, leukemia, anemia, and cardiovascular biology. Delineating the mechanism(s) whereby Samd14 facilitates c-Kit downstream of GATA may reveal therapeutic strategies for treating hematologic and vascular disorders.
Networks of cis-regulatory elements are essential for controlling blood cell regeneration and disease.
Another goal is to discover cis-element circuits/networks that confer stem cell function in regenerative contexts such as acute/chronic anemia and blood/cardiovascular disorders. In addition to the Samd14-Enh, several GATA-Factor-occupied, Samd14-Enh-like loci are similarly upregulated in anemia, suggesting a mechanism in which a GATA-2/anemia-regulated genetic network is required for restoring homeostasis under conditions of anemia. We hypothesize that Samd14-Enh is a founding member of an ensemble of anemia-sensing enhancers.
We are looking for talented, curious students and postdocs. Our collaborative approaches use cutting-edge genetic and molecular tools, including gene editing (using CRISPR/Cas9), shRNA knockdown, flow cytometry and novel murine disease models. We value active hands-on training and mentoring, and expect that students develop constructive critical thinking skills to guide their individual lab projects. These skills apply to many areas of academic and professional life.
- Peng Y, Shapiro SL, Banduseela VC, Dieterich IA, Hewitt KJ, Bresnick EH, Kong G, Zhang J, Schueler KL, Keller MP, Attie AD, Hacker TA, Sullivan R, Kielar-Grevstad E, Arriola Apelo SI, Lamming DW, Anderson RM, Puglielli L. Increased transport of acetyl-CoA into the endoplasmic reticulum causes a progeria-like phenotype. Aging cell. 2018; :e12820.
- Bresnick EH, Hewitt KJ, Mehta C, Keles S, Paulson RF, Johnson KD. Mechanisms of erythrocyte development and regeneration: implications for regenerative medicine and beyond. Development (Cambridge, England). 2018; 145(1). PubMed [journal] PMID: 29321181, PMCID: PMC5825862
- McIver SC, Hewitt KJ, Gao X, Mehta C, Zhang J, Bresnick EH. Dissecting Regulatory Mechanisms Using Mouse Fetal Liver-Derived Erythroid Cells. Methods in molecular biology (Clifton, N.J.). 2018; 1698:67-89.
- Hewitt KJ, Katsumura KR, Matson DR, Devadas P, Tanimura N, Hebert AS, Coon JJ, Kim JS, Dewey CN, Keles S, Hao S, Paulson RF, Bresnick EH. GATA Factor-Regulated Samd14 Enhancer Confers Red Blood Cell Regeneration and Survival in Severe Anemia. Developmental cell. 2017; 42(3):213-225.e4.
- Hewitt KJ, Johnson KD, Gao X, Keles S, Bresnick EH. The Hematopoietic Stem and Progenitor Cell Cistrome: GATA Factor-Dependent cis-Regulatory Mechanisms. Current topics in developmental biology. 2016; 118:45-76.
- Johnson KD, Kong G, Gao X, Chang YI, Hewitt KJ, Sanalkumar R, Prathibha R, Ranheim EA, Dewey CN, Zhang J, Bresnick EH. Cis-regulatory mechanisms governing stem and progenitor cell transitions. Science advances. 2015; 1(8):e1500503.
- Hewitt KJ, Kim DH, Devadas P, Prathibha R, Zuo C, Sanalkumar R, Johnson KD, Kang YA, Kim JS, Dewey CN, Keles S, Bresnick EH. Hematopoietic Signaling Mechanism Revealed from a tem/Progenitor Cell Cistrome. Molecular cell. 2015; 59(1):62-74.
- Hewitt KJ, Shamis Y, Gerami-Naini B, Garlick JA. Strategies for Oral Mucosal Repair by Engineering 3D Tissues with Pluripotent Stem Cells. Advances in wound care. 2014; 3(12):742-750.
- Hewitt KJ, Sanalkumar R, Johnson KD, Keles S, Bresnick EH. Epigenetic and genetic mechanisms in red cell biology. Current opinion in hematology. 2014; 21(3):155-64.
- Sanalkumar R, Johnson KD, Gao X, Boyer ME, Chang YI, Hewitt KJ, Zhang J, Bresnick Mechanism governing a stem cell-generating cis-regulatory element. Proceedings of the National Academy of Sciences of the United States of America. 2014; 111(12):E1091-100.
- Hewitt KJ, Garlick JA. Cellular reprogramming to reset epigenetic signatures. Molecular aspects of medicine. 2013; 34(4):841-8.
- Hewitt KJ, Shamis Y, Knight E, Smith A, Maione A, Alt-Holland A, Sheridan SD, Haggarty SJ, Garlick JA. PDGFRβ expression and function in fibroblasts derived from pluripotent cells is linked to DNA demethylation. Journal of cell science. 2012; 125(Pt 9):2276-87.
- Hewitt KJ, Shamis Y, Hayman RB, Margvelashvili M, Dong S, Carlson MW, Garlick JA. Epigenetic and phenotypic profile of fibroblasts derived from induced pluripotent stem cells. PloS one. 2011; 6(2):e17128.
- Hewitt KJ, Shamis Y, Carlson MW, Aberdam E, Aberdam D, Garlick JA. Three-dimensional epithelial tissues generated from human embryonic stem cells. Tissue engineering. Part A. 2009; 15(11):3417-26.
- Dissanayake SK, Olkhanud PB, O'Connell MP, Carter A, French AD, Camilli TC, Emeche CD, Hewitt KJ, Rosenthal DT, Leotlela PD, Wade MS, Yang SW, Brant L, Nickoloff BJ, Messina JL, Biragyn A, Hoek KS, Taub DD, Longo DL, Sondak VK, Hewitt SM, Weeraratna AT. Wnt5A regulates expression of tumor-associated antigens in melanoma via changes in signal transducers and activators of transcription 3 phosphorylation. Cancer research. 2008; 68(24):10205-14.22.
- Hewitt KJ, Agarwal R, Morin PJ. The claudin gene family: expression in normal and neoplastic tissues. BMC cancer. 2006; 6:186