Center for Gene Regulation in Health and Disease (GRHD)

Merlin Nithya Gnanapragasam

The overarching goal of the laboratory is to delineate the processes that regulate tissue proliferation and differentiation, and how dysregulation of these pathways contributes to human diseases. Our studies utilize erythroid cells as a model system.

Enucleated red blood cells constitute 80% of cells in the body. A precise balance between self-renewal divisions and terminal differentiation is essential for maintaining this enormous pool of cells. Terminal erythroid differentiation is particularly unique in that the differentiation program is coupled to 3-4 rapid terminal cell divisions with peculiarly short G1 phase and fast DNA replication compared to self-renewal divisions. We do not yet understand the processes that regulate the timing, integrity, and the numbers of these rapid terminal divisions. Dysregulation of these terminal divisions leads to impairment of terminal erythroid differentiation and diseases such as Congenital Dyserythropoietic Anemia (CDA), a severe anemia characterized by increased proportions of binucleated erythrocytes.

Our current research goals are twofold: 1) Understand how the specialized transcriptional regulation in erythroid cells ensures that the cell cycle machinery is able to accommodate the rapid pace of the terminal cell divisions. Specifically, our lab will investigate how ubiquitous factors regulating DNA replication, centromere cohesion, and cytokinesis, cater to the specialized demands of the rapid erythroid cell divisions. 2) Investigate the molecular pathogenesis of CDA IV, which is a severe anemia caused by a hypomorphic mutation in EKLF/KLF1 (a master regulator of erythropoiesis), that arises due to a failure in terminal cell divisions and result in binucleate erythroblasts and erythroblasts with DNA bridges.

We are also interested in understanding the mechanisms of hemoglobin switching. An attractive therapeutic strategy to ameliorate and potentially cure beta thalassemia and sickle cell anemia is to manipulate the globin gene regulation by exploiting the biology behind hemoglobin switching. One of our goals is to identify factors that induce fetal hemoglobin in adult erythroid cells due to its ameliorating effects in these anemias.

Complete List of Published Work in MyBibliography

Selected Publications:

1.     Gnanapragasam MN, Crispino JD, Ali AM, Weinberg R, Hoffman R, Raza A, Bieker JJ. Survey and evaluation of mutations in the human KLF1 transcription unit. Sci Rep. 2018 Apr 26;8(1):6587.

2.     Gnanapragasam MN, Bieker JJ. Orchestration of late events in erythropoiesis by KLF1/EKLF. Curr Opin Hematol. 2017 May;24(3):183-190.

3.     Gnanapragasam MN, McGrath KE, Catherman S, Xue L, Palis J, Bieker JJ. EKLF/KLF1-regulated cell cycle exit is essential for erythroblast enucleation. Blood. 2016 Sep 22;128(12):1631-41. (Highlighted in Hematopoiesis News).

4.     Liang R, Campreciós G, Kou Y, McGrath K, Nowak R, Catherman S, Bigarella CL, Rimmelé P, Zhang X, Gnanapragasam MN, Bieker JJ, Papatsenko D, Ma'ayan A, Bresnick E, Fowler V, Palis J, Ghaffari S. A Systems Approach Identifies Essential FOXO3 Functions at Key Steps of Terminal Erythropoiesis. PLoS Genet. 2015 Oct 9;11(10).

5.     *Yien YY, *Gnanapragasam MN, Gupta R, Rivella S, Bieker JJ. Alternative splicing of EKLF/KLF1 in murine primary erythroid tissues. Exp Hematol. 2015 Jan;43(1):65-70. (*Authors contributed equally).

6.    Xue L, Galdass M, Gnanapragasam MN, Manwani D, Bieker JJ. Extrinsic and intrinsic control by EKLF (KLF1) within a specialized erythroid niche. Development. 2014 Jun;141(11):2245-54.

7.     Jaffray JA, Mitchell WB, Gnanapragasam MN, Seshan SV, Guo X, Westhoff CM, Bieker JJ, Manwani D. Erythroid transcription factor EKLF/KLF1 mutation causing congenital dyserythropoietic anemia type IV in a patient of Taiwanese origin: review of all reported cases and development of a clinical diagnostic paradigm. Blood Cells Mol Dis. 2013 Aug;51(2):71-5

8.     Amaya M, Desai M, Gnanapragasam MN, Wang SZ, Zu Zhu S, Williams DC Jr, Ginder GD. Mi2β-mediated silencing of the fetal γ-globin gene in adult erythroid cells. Blood. 2013 Apr 25;121(17):3493-501.

9.     Mian OY, Wang SZ, Zhu SZ, Gnanapragasam MN, Graham LJ, Bear HD, Ginder GD. Methyl Binding Domain Protein 2 (MBD2) Dependent Proliferation and Survival of Breast Cancer Cells. Mol Cancer Res. 2011;9(8):1152-62.

10.  Gnanapragasam MN, Scarsdale JN, Amaya ML, Webb HD, Desai MA, Walavalkar NM, Wang SZ, Zu Zhu S, Ginder GD, Williams DC Jr. p66Alpha-MBD2 coiled-coil interaction and recruitment of Mi-2 are critical for globin gene silencing by the MBD2-NuRD complex. Proc Natl Acad Sci U S A. 2011 May 3;108(18):7487-92.

11.  Rupon JW, Wang SZ, Gnanapragasam M, Labropoulos S, Ginder GD. MBD2 contributes to developmental silencing of the human ε-globin gene. Blood Cells Mol Dis. 2011 Mar 15;46(3):212-9.

12.  Ginder GD, Gnanapragasam MN, Mian OY. The role of the epigenetic signal, DNA methylation, in gene regulation during erythroid development. Curr Top Dev Biol. 2008;82:85-116.