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.
- Ray, S., Chee, L., Zhou, Y., Schaefer, M.A., Naldrett, M.J., Alvarez, S., Woods, N.T., Hewitt, K.J., Functional Requirements for a Samd14-Capping Protein Complex in Stress Erythropoiesis. eLife, 2022 (doi: 12.31.474625).
- Ray, S., Chee, L., Matson, D.R., Palermo, N.Y., Bresnick, E.H., and Hewitt K.J. Sterile alpha motif domain requirement for cellular signaling and survival. J Biol Chem. 2020 Apr 2.
- Katsumura KR, Mehta C, Hewitt KJ, Soukup AA, Fraga de Andrade I, Ranheim EA, Johnson KD, Bresnick EH. Human leukemia mutations corrupt but do not abrogate GATA-2 function. Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):E10109-E10118. PMID: 30301799
- Peng Y., Shapiro S.L., Banduseela V.C., Dieterich I.A., Hewitt K.J., Bresnick E.H., Kong G., Zhang J., Schueler K.L., Keller M.P., Attie A.D., Hacker T.A., Sullivan R., Kielar-Grevstad E., Arriola Apelo S.I., Lamming D.W., Anderson R.M., Puglielli L. Increased transport of acetyl-CoA into the endoplasmic reticulum causes a progeria-like phenotype. Aging Cell. 2018 Jul 27:e12820. doi: 10.1111/acel.12820. PMID: 30051577
- Hewitt, K.J., Katsumura, K.R., Matson, D.R., Devadas, P., Tanimura, N. Hebert, A.S., Coon, J.J., Kim, J.S., Dewey, C.N., Keles, S., Hao, S., Paulson, R.F., Bresnick, E.H. GATA Factor-Regulated Samd14 Enhancer Confers Red Blood Cell Regeneration and Survival in Severe Anemia. Dev Cell. 2017. August 7; 42. PMID:28787589
- Zuo, C., Chen, K., Hewitt, K.J., Bresnick, E.H., and Keleş, S. A hierarchical framework for state-space matrix inference and clustering. Ann. Appl. Stat. 2016 Sept 28;10(3):1348-1372.
- Johnson K.D., Kong G., Gao X., Chang Y.I., Hewitt K.J., Sanalkumar R., Prathibha R., Ranheim E.A., Dewey C.N., Zhang J., Bresnick E.H. Cis-regulatory mechanisms governing stem and progenitor cell transitions. Sci Adv. 2015 Sep 4;1(8): e1500503. PMID: 26601269
- Hewitt K.J., Kim D.H., Devadas P., Prathibha R., Zuo C., Sanalkumar R., Johnson K.D., Kang Y.A., Kim J.S., Dewey C.N., Keles S., and Bresnick E.H. Hematopoietic Signaling Mechanism Revealed From a Stem/Progenitor Cell Cistrome. Mol Cell. 2015 Jul 2;59(1):62-74. PMID: 26073540
- McIver S.C., Hewitt K.J., Gao X., Mehta C., Zhang J., Bresnick E.H. Dissecting Regulatory Mechanisms Using Mouse Fetal Liver-Derived Erythroid Cells. Methods Mol Biol. 2018;1698:67-89. doi: 10.1007/978-1-4939-7428-3_4. PMID: 29076084
- Katsumura K.R., Gao, X., Hewitt, K.J., Matson, D.R., McIver, S.C., Mehta, C., Soukup, A.A., Tanimura, N, Shi, L., Johnson, K.D., Bresnick E.H. The GATA factor revolution in hematology. Blood. 2017 Feb 8. PMID: 28179282
- Hewitt K.J., Johnson K.D., Gao X., Keles S., Bresnick E.H. The Hematopoietic Stem and Progenitor Cell Cistrome: GATA Factor-Dependent cis-Regulatory Mechanisms. Curr Top Dev Biol. 2016;118:45-76. PMID: 27137654
- Hewitt K.J., Sanalkumar R., Johnson K.D., Keles S., Bresnick E.H. Epigenetic and genetic mechanisms in red cell biology. Curr Opin Hematol. 2014 May;21(3):155-64. PMID: 24722192