Sridhar Rao, MD, PhD

Stem Cell Biology / Hematopoiesis

The primary focus of our lab is to understand how changes in gene expression influence differentiation of stem cells. Alterations in this process are a key step in the development of leukemia. In particular, our laboratory focuses on how non-coding DNA elements act as “molecular switches” to causes changes in gene expression. We use different models to understand how non-coding DNA elements regulate which genes are on or off in a particular cell type, but one of our primary models is Acute Myeloid Leukemia (AML). We focus on AML because it has a poor long-term survival even with high dose chemotherapy, illustrating the need for more effective, less toxic therapies. In AML, approximately 15% of patients have mutations within genes encoding the cohesin complex, which plays a critical role in allowing non-coding DNA elements to regulate gene expression. In addition to AML, we also use mouse derived stem cells to ask fundamental questions about how non-coding DNA elements regulate gene expression. Most of our studies rely upon next-generation sequencing-based genome wide approaches, in addition to genomic editing to understand how non-coding DNA elements regulate stem cell differentiation.

• Rao (PI)  5R01CA204231-02  09/19/2017 – 07/31/2022  NIH/NCI  Cohesin mutations in AML  
  The goal of this project is to understand the role of cohesin protein in the progression of AML.  
• Rao (Co-I)  MCW/MACC Fund Support  07/01/2019 – 06/30/2020  MCW/MACC Fund  High-Risk Hematologic Malignancy Center  
  This is an internal funding mechanism to support the the integration of ongoing clinical trials, translational efforts, and basic researchers to improve the care of children with hematologic malignancies. The bulk of the fund provides support for biological correlative studies related to Dr. Burke’s (PI) TACL trial.

Kirthi Pulakanti
Bioinformatics Analyist 

Quinn Furomo
Bioinformatics Analyist

Alison Nickerson
Research Scientist I

Cary Stelloh
Research Technologist

Katelyn Heimbruch
Graduate Student

Puja Agarwal
Graduate Student

Kristin Zorn
Clinical Fellow

• Rao S (2012). Embryonic Stem Cells: a perfect tool for studying mammalian transcriptional enhancers. J Stem Cell Res Ther, S10-007, PMCID3844140
• Blinka S, MH Reimer, K Pulakanti, L Pinello, GC Yuan, and S Rao (2017). Identification of Transcribed Enhancers by Genome-Wide Chromatin Immunoprecipitation Sequencing. Methods in Molecular Biology, Enhancer RNAs. Series Editor: John Walker; Book Editor: Ulf Andersson Orom. 1468:91-109 PMID27662872
• Fisher JB, M McNulty, MJ Burke, JD Crispino, and S Rao (2017). Cohesin Mutations in Myeloid Malignancies. Trends in Cancer, 3:282-293 PMCID in process.
• Blinka S and S Rao (2017). Nanog Expression in Embryonic Stem Cells-an Ideal Model System to Dissect Enhancer Function. BioEssays. Manuscript accepted
• Pulakanti K, L Pienello, C Stelloh, S Blinka, J Allred, S Milanovich, S Kiblawi, J Peterson, A Wang, GC Yuan*, and S Rao* (2013). Enhancer transcribed RNAs arise from hypomethylated, Tet-occupied genomic regions. Epigenetics 8:1303–1320. PMCID:3933491 *co-senior authors
• Boehler KR, S Bhattacharya, EM Kropp, S Chuppa, DR Riordon, D Bausch-Fluck, PW Burridge, JC Wu, RP Wersto, GC Chan, S Rao, B Wollscheid, and RL Gundry (2014). A human pluripotent stem cell surface N-glycoproteome resource reveals new markers, extracellular epitopes, and drug targets. Stem Cell Reports\ 3:185-203. PMCID:4110789
• Milanovich S, J Peterson, J Allred, C Stelloh, K Rajasekaran, J Fisher, SA Duncan, S Malarkannan, and S Rao (2015). Sall4 overexpression blocks murine hematopoiesis in a dose-dependent manner. Exp Hematology 43:53-64. PMCID:4268405
• Sohni A, M Bartoccetti, R Khoueiry, L Spans, J Vande Velde, L De Troyer, K Pulakanti, F Claessens, S Rao, and KP Koh (2015). Dynamic switching of active promoter and enhancer domains regulates Tet1 and Tet2 expression during cell state transitions between pluripotency and differentiation. Mol Cell Bio 35:1026-1042. PMCID:4333094
• Zhang N, H Zhi, BR Curtis, S Rao, C Jobaliya, M Poncz, DL French, and PJ Newman (2016). CRISPR/Cas9-mediated conversion of human platelet alloantigen allotypes. Blood, 127:675-80. PMCID:4751021
• Stelloh C, MH Reimer, K Pulakanti, S Blinka, J Peterson, L Pinello, S Jia, S Roumiantsev, MJ Hessner, S Milanovich, GC Yuan, and S Rao (2016). The cohesin-associated protein Wapal is required for proper polycomb-mediated gene silencing. Epigenetics and Chromatin 9:14. PMCID:4832553
• Blinka S, MH Reimer, K Pulakanti, and S Rao (2016). Super-Enhancers at the Nanog Locus Differentially Regulate Neighboring Pluripotency-Associated Genes. Cell Reports 17:19-28. PMCID:5111363
• Swartz KL, SN Woods, T Murthy, O Ramirez, G Qin, MM Pillai, S Rao, and AC Minella (2017) E2F-2 promotes nuclear condensation and enucleation of terminally differentiated erythroblasts. Mol Cell Biol 37:e00274-16. PMCID:5192079
• Fisher J, J Peterson, M Reimer, C Stelloh, K Pulakanti, ZJ Gerbec, AM Abel, J Strouse-Miksanek, C Strouse, M McNulty, S Malarkannan, JD Crispino, S Milanovich, and S Rao (2017). The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of HoxA7 and HoxA9. Leukemia 31:712-719. PMID:27554164
• Thompson CA, K Wojta, K Pulakanti, S Rao, P Dawson, and MA Battle M.A (2017). GATA4 is sufficient to establish jejunal versus ileal identity in the small intestine. Cell Mol Gastroenterology Hepatology. 3:422-446 PMCID5404030
• Fisher JB, Pulakanti K, Rao S, Duncan SA. GATA6 is essential for endoderm formation from human pluripotent stem cells. Biol Open. 2017;6(7):1084. PMCID: PMC5550920
• Jing W, Gershan JA, Holzhauer S, Weber J, Palen K, McOlash L, Pulakanti K, Wesley E, Rao S, Johnson BD, Riese MJ. T cells deficient in diacylglycerol kinase ζ are resistant to PD-1 inhibition and help create persistent host immunity to leukemia. Cancer Res. 2017;77(20):5676. PMID: 28916658
• Broglie L, Pommert L, Rao S, Thakar M, Phelan R, Margolis D, Talano J. Ruxolitinib for treatment of refractory hemophagocytic lymphohistiocytosis. Blood Adv. 2017 Aug 22;1(19):1533-1536. PMCID: PMC5728466
• Nanbakhsh A, Best B, Riese M, Rao S, Wang L, Medin J, Thakar MS, Malarkannan S. Dextran enhances the lentiviral transduction efficiency of murine and human primary NK Cells. J Vis Exp. 2018; 15(131):55063. PMCID: PMC5908645
• Newman DK, Fu G, McOlash L, Schauder D, Newman PJ, Cui W, Rao S, Johnson BD, Gershan JA, Riese MJ. Frontline Science: PECAM-1 (CD31) expression in naïve and memory, but not acutely activated, CD8 T cells. J Leukoc Biol. 2018;104(5):883. PMCID: PMC6195461
• Murthy T, Bluemn T, Gupta AK, Reimer M Jr, Rao S, Pillai MM, Minella AC. Cyclin-dependent kinase 1 (CDK1) and CDK2 have opposing roles in regulating interactions of splicing factor 3B1 with chromatin. J Biol Chem. 2018;293(26):10220. PMCID: PMC6028971
• Volk A, Liang K, Suraneni P, Li X, Zhao J, Bulic M, Marshall S, Pulakanti K, Malinge S, Taub J, Ge Y, Rao S, Bartom E, Shilatifard A, Crispino JD. A CHAF1B-dependent molecular switch in hematopoiesis and leukemia pathogenesis. Cancer Cell. 2018;34(5):707;e7. PMCID: PMC6235627
• Stoltz KP, Jondle CN, Pulakanti K, Sylvester PA, Urrutia R, Rao S*, Tarakanova VL*. Tumor suppressor interferon regulatory factor 1 selectively blocks expression of endogenous retrovirus. Virology. 2019;526:52. PMCID: PMC6875439 *co-corresponding authors
• Gupta AK, Murthy T, Paul KV, Ramirez O, Fisher JB, Rao S, Rosenberg AB, Seelig G, Minella AC, Pillai MM. Degenerate minigene library analysis enables identification of altered branch point utilization by mutant splicing factor 3B1 (SF3B1). Nucleic Acids Res. 2019;47(2):970. PMCID: PMC6344872
• DeLaForest A, Di Furio F, Jing R, Ludwig-Kubinski A, Twaroski K, Urick A, Pulakanti K, Rao S, Duncan SA. HNF4A regulates the formation of hepatic progenitor cells from human iPSC-derived endoderm by facilitating efficient recruitment of RNA pol II. Genes (Basel). 2018;10(1):21. PMCID: PMC6356828
• Ray A, Khalil MI, Pulakanti KL, Burns RT, Gurski CJ, Basu S, Wang D, Rao S, Dittel BN. Mature IgD B cells maintain tolerance by promoting regulatory T cell homeostasis. Nat Commun. 2019;10(1):190. PMCID: PMC6331566
• Izaguirre-Carbonell J, Christiansen L, Burns R, Schmitz J, Li C, Mokry RL, Bluemn T, Zheng Y, Shen J, Carlson KS, Rao S, Wang D, Zhu N. Critical role of jumonji domain of JMJD1C in MLL-rearranged leukemia. Blood Adv. 2019;3(9):1499. PMCID: PMC6517669
• Reimer M Jr, Pulakanti K, Shi L, Abel A, Liang M, Malarkannan S, Rao S. Deletion of tet proteins results in quantitative disparities during ESC differentiation partially attributable to alterations in gene expression. BMC Dev Biol. 2019;19(1):16. PMCID: PMC6615237
• Yang C, Siebert JR, Burns R, Gerbec ZJ, Bonacci B, Rymaszewski A, Rau M, Riese MJ, Rao S, Carlson KS, Routes JM, Verbsky JW, Thakar MS, Malarkannan S. Heterogeneity of human bone marrow and blood natural killer cells defined by single-cell transcriptome. Nat Commun. 2019;10(1):3931. PMCID: PMC6718415
• Gao C, Schroeder JA, Xue F, Jing W, Cai Y, Scheck A, Subramaniam S, Rao S, Weiler H, Czechowicz A, Shi Q. Nongenotoxic antibody-drug conjugate conditioning enables safe and effective platelet gene therapy of hemophilia A mice. Blood Adv. 2019;3(18):2700. PMCID: PMC6759737
• Nanbakhsh A, Srinivasamani A, Holzhauer S, Riese MJ, Zheng Y, Wang D, Burns R, Reimer MH, Rao S, Lemke A, Tsaih SW, Flister MJ, Lao S, Dahl R, Thakar MS, Malarkannan S. Mirc11 disrupts inflammatory but not cytotoxic responses of NK Cells. Cancer Immunol Res. 2019;7(10):1647. PMCID: PMC7428857
• Mishra MK, Liang EY, Geurts AM, Auer PWL, Liu P, Rao S, Greene AS, Liang M, Liu Y. Comparative and functional genomic resource for mechanistic studies of human blood pressure-associated single nucleotide polymorphisms. Hypertension. 2020;75(3):859. PMCID: PMC7035167
• Dausinas P, Pulakanti K, Rao S, Cole JM, Dahl R, Cowden Dahl KD. ARID3A and ARID3B induce stem promoting pathways in ovarian cancer cells. Gene. 2020;738:144458. PMCID: PMC7384259 (available on 2021-05-15)
• Yang C, Siebert JR, Burns R, Zheng Y, Mei A, Bonacci B, Wang D, Urrutia RA, Riese MJ, Rao S, Carlson KS, Thakar MS, Malarkannan S. Single-cell transcriptome reveals the novel role of T-bet in suppressing the immature NK gene signature. Elife. 2020;9. PMCID: PMC7255804
• Meyer AE, Furumo Q, Stelloh C, Minella AC, Rao S. Loss of Fbxw7 triggers mammary tumorigenesis associated with E2F/c-Myc activation and Trp53 mutation. Neoplasia. 2020. In press