Cell Differentiation; Hematologic Diseases; Hematopoiesis; Neoplasms; Cell Lineage
Stem Cell Center, Yale: Stem Cell Self-Renewal and Cell Symmetry | Transcriptional Regulation of Stem and Progenitor Cells
We are interested in using genomics to understand the role of non-coding RNAs in mammalian development and disease. Currently, we are focusing on the following topics. 1. Non-coding RNAs in blood stem cell differentiation and malignancies 2. MicroRNA-mediated control of embryonic stem cell fates 3. MicroRNA mechanisms.
Extensive Research Description
completion of the human genome project leads to the realization that
only a small percentage of our heritable DNA sequences encodes
proteins. Instead of being “junk DNA”, a significant portion of the
genome is transcribed into the so-called non-coding RNAs. Emerging
pieces of evidence indicate that these RNA molecules, although lacking
protein-coding capacity, play important roles in regulating the genomic
output. MicroRNAs are one class of tiny non-coding RNAs that are ~21
nucleosides in length and are often highly conserved among species.
They recognize sites in messenger RNAs, and by doing so, regulate
translation and/or target mRNA abundance.
In our laboratory, we aim to understand how microRNAs and other non-coding RNAs regulate mammalian cell fate choices during differentiation, and how alterations in such regulations lead to human diseases, with an emphasis on cancer. We use the blood system as one of our models. Hematopoietic stem cells undergo a series of fate choices during its differentiation to give rise to all mature blood cells, whereas changes in the differentiation program can cause malignancies such as leukemia. We use a set of genomic tools to dissect how microRNAs may control these processes. We combine the information from genome-wide microRNA expression analyses and microRNA functional genomics screens to derive candidates for functional characterization. In addition, we study the role of large non-coding RNAs in these processes.
Another area of interest is the differentiation of embryonic stem cells. ES cells and induced pluripotent cells possess the ability to differentiate into all cell types , holding the promise for cell replacement therapy. MicroRNAs are dynamically regulated during ES cell differentiation. In addition, we have shown that microRNAs direct mammalian lineage choices. Projects in the lab aim to understand the role of microRNAs in modulating the differentiation outcome of ES cells.
We are also interested to use bioinformatics to understand basic microRNA mechanisms. A current project focuses on the analysis of common microRNA and messenger RNA profiling data from a large cohort of samples, aiming to derive rules on microRNA biogenesis, termination and crosstalk with canonical protein-coding gene pathways.
An Extensive Network of TET2-Targeting microRNAs Regulates Malignant Hematopoiesis.
Jijun Cheng, Shangqin Guo, Suning Chen, Stephen Mastriano, Chaochun Liu, Ana D’Alessio, Eriona Hysolli, Yanwen Guo, Hong Yao, Cynthia Megyola, Dan Li, Jun Liu, Wen Pan, Christine Roden, Kartoosh Heydari, Jianjun Chen, In-Hyun Park, Ye Ding, Yi Zhang, and Jun Lu. An Extensive Network of TET2-Targeting microRNAs Regulates Malignant Hematopoiesis. Cell Reports, 5:1-11, 2013
An In Vivo Functional Screen Uncovers miR-150-Mediated Regulation of Hematopoietic Injury Response.
Brian D. Adams, Shangqin Guo, Haitao Bai, Yanwen Guo, Cynthia Megyola, Jijun Cheng, Kartoosh Heydari, Changchun Xiao, E. Premkumar Reddy, and Jun Lu. An In Vivo Functional Screen Uncovers miR-150-Mediated Regulation of Hematopoietic Injury Response. Cell Reports, 2(4):1048-1060, 2012
Non-stochastic reprogramming from a privileged somatic cell state.
Shangqin Guo*, Xiaoyuan Zi, Vince Schultz, Mei Zhong, Jijun Cheng, Sebastian Koochaki, Cynthia M. Megyola, Xinghua Pan, Kartoosh Heydari, Sherman M. Weissman, Patrick G. Gallagher, Diane S. Krause, Rong Fan, and Jun Lu. Non-stochastic reprogramming from a privileged somatic cell state. Cell, 156(4): 649-62, 2014.
Complex oncogene dependence in microRNA-125a-induced myeloproliferative neoplasms.
Shangqin Guo, Haitao Bai, Cynthia Megyola, Stephanie Halene, Diane S. Krause, David T. Scadden and Jun Lu. Complex oncogene dependence in microRNA-125a-induced myeloproliferative neoplasms. PNAS, 2012
MicroRNA expression profiles classify human cancers.
Jun Lu, Gad Getz, Eric A. Miska, Ezequiel A. Alvarez-Saavedra, Justin Lamb, David Peck, Alejandro Sweet-Cordero, Benjamin L. Ebert, Raymond H. Mak, Adolfo A. Ferrando, James R. Downing, Tyler Jacks, H. Robert Horvitz and Todd R. Golub. MicroRNA expression profiles classify human cancers. Nature, 435(7043):834-8, 2005
Scadden and Todd R. Golub. microRNA-mediated control of of cell fate in megakaryocyte-erythrocyte progenitors.
Jun Lu, Shangqin Guo, Benjamin L. Ebert, Hao Zhang, Xiao Peng, Jocelyn Bosco, Jennifer Pretz, Rita Schlanger, Judy H. Wang, Raymond H. Mak, David M. Dombkowski, Frederic I. Preffer, David T. Scadden and Todd R. Golub. microRNA-mediated control of of cell fate in megakaryocyte-erythrocyte progenitors. Developmental Cell, 14(6):843-53, 2008
Distinct microRNA expression profiles in acute myeloid leukemia with common translocations.
Zejuan Li, Jun Lu (co-first author), Miao Sun, Shuangli Mi, Hao Zhang, Roger T. Luo, Zhijian Qian, Mary Beth Neilly, Yungui Wang, Jie Jin, Yanming Zhang, Stefan K. Bohlander, Richard Larson, Michelle Le Beau, Michael J. Thirman, Todd R. Golub, Janet D. Rowley, and Jianjun Chen. MicroRNA expression profiles distinguish common translocations in AML. PNAS, 105(40): 15535-40, 2008
MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia.
Shuangli Mi, Jun Lu (co-first author), Miao Sun, Zejuan Li, Hao Zhang, Mary Beth Neilly, Yungui Wang, Zhijian Qian, Jie Jin, Yanming Zhang, Stefan K. Bohlander, Michelle M. LeBeau, Richard A. Larson, Todd R. Golub, Janet D. Rowley and Jianjun Chen. MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia. PNAS, 104(50):19971-6, 2007
MicroRNA miR-125a controls hematopoietic stem cell number.
Guo S, Lu J (co-first), Schlanger R, Zhang H, Wang JY, Fox MC, Purton LE, Fleming HH, Cobb B, Merkenschlager M, Golub TR, Scadden DT, MicroRNA miR-125a controls hematopoietic stem cell number, PNAS, 107(32):14229-34, 2010
Systematic discovery of regulatory motifs in human promoters and 3’ UTRs by comparison of several mammals.
Xiaohui Xie, Jun Lu, E. J. Kulbokas, Todd R. Golub, Vamsi Mootha, Kerstin Lindblad-Toh, Eric S. Lander and Manolis Kellis. Systematic discovery of regulatory motifs in human promoters and 3’ UTRs by comparison of several mammals. Nature, 434 (7031):338-45, 2005
Full List of PubMed Publications
- Liu J, Guo B, Chen Z, Wang N, Iacovino M, Cheng J, Roden C, Pan W, Khan S, Chen S, Kyba M, Fan R, Guo S, Lu J: miR-125b promotes MLL-AF9-driven murine acute myeloid leukemia involving a VEGFA-mediated non-cell-intrinsic mechanism. Blood. 2017 Mar 16; 2017 Jan 4. PMID: 28053194
- Vuckovic S, Vandyke K, Rickards DA, McCauley Winter P, Brown SH, Mitchell TW, Liu J, Lu J, Askenase PW, Yuriev E, Capuano B, Ramsland PA, Hill GR, Zannettino AC, Hutchinson AT: The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells. Br J Haematol. 2017 Feb 17; 2017 Feb 17. PMID: 28211573
- Roden C, Gaillard J, Kanoria S, Rennie W, Barish S, Cheng J, Pan W, Liu J, Cotsapas C, Ding Y, Lu J: Novel determinants of mammalian primary microRNA processing revealed by systematic evaluation of hairpin-containing transcripts and human genetic variation. Genome Res. 2017 Mar; 2017 Jan 13. PMID: 28087842
- Liddicoat BJ, Hartner JC, Piskol R, Ramaswami G, Chalk AM, Kingsley PD, Sankaran VG, Wall M, Purton LE, Seeburg PH, Palis J, Orkin SH, Lu J, Li JB, Walkley CR: Adenosine-to-inosine RNA editing by ADAR1 is essential for normal murine erythropoiesis. Exp Hematol. 2016 Oct; 2016 Jul 1. PMID: 27373493
- Roden C, Lu J: MicroRNAs in Control of Stem Cells in Normal and Malignant Hematopoiesis. Curr Stem Cell Rep. 2016 Sep; 2016 Jul 1. PMID: 27547713
- Narayanan A, Hill-Teran G, Moro A, Ristori E, Kasper DM, A Roden C, Lu J, Nicoli S: In vivo mutagenesis of miRNA gene families using a scalable multiplexed CRISPR/Cas9 nuclease system. Sci Rep. 2016 Aug 30; 2016 Aug 30. PMID: 27572667
- Hysolli E, Tanaka Y, Su J, Kim KY, Zhong T, Janknecht R, Zhou XL, Geng L, Qiu C, Pan X, Jung YW, Cheng J, Lu J, Zhong M, Weissman SM, Park IH: Regulation of the DNA Methylation Landscape in Human Somatic Cell Reprogramming by the miR-29 Family. Stem Cell Reports. 2016 Jul 12; 2016 Jun 30. PMID: 27373925
- Gonzalez-Martin A, Adams BD, Lai M, Shepherd J, Salvador-Bernaldez M, Salvador JM, Lu J, Nemazee D, Xiao C: The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunity. Nat Immunol. 2016 Apr; 2016 Feb 22. PMID: 26901150
- Cheng J, Roden CA, Pan W, Zhu S, Baccei A, Pan X, Jiang T, Kluger Y, Weissman SM, Guo S, Flavell RA, Ding Y, Lu J: A Molecular Chipper technology for CRISPR sgRNA library generation and functional mapping of noncoding regions. Nat Commun. 2016 Mar 30; 2016 Mar 30. PMID: 27025950
- Lechman ER, Gentner B, Ng SW, Schoof EM, van Galen P, Kennedy JA, Nucera S, Ciceri F, Kaufmann KB, Takayama N, Dobson SM, Trotman-Grant A, Krivdova G, Elzinga J, Mitchell A, Nilsson B, Hermans KG, Eppert K, Marke R, Isserlin R, Voisin V, Bader GD, Zandstra PW, Golub TR, Ebert BL, Lu J, Minden M, Wang JC, Naldini L, Dick JE: miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells. Cancer Cell. 2016 Feb 8; 2016 Jan 28. PMID: 26832662
- Kanoria S, Rennie W, Liu C, Carmack CS, Lu J, Ding Y: STarMir Tools for Prediction of microRNA Binding Sites. Methods Mol Biol. 2016. PMID: 27665594
- Guo Y, Liu J, Elfenbein SJ, Ma Y, Zhong M, Qiu C, Ding Y, Lu J: Characterization of the mammalian miRNA turnover landscape. Nucleic Acids Res. 2015 Feb 27; 2015 Feb 4. PMID: 25653157
- Zhang PX, Cheng J, Zou S, D'Souza AD, Koff JL, Lu J, Lee PJ, Krause DS, Egan ME, Bruscia EM: Pharmacological modulation of the AKT/microRNA-199a-5p/CAV1 pathway ameliorates cystic fibrosis lung hyper-inflammation. Nat Commun. 2015 Feb 10; 2015 Feb 10. PMID: 25665524
- Roden C, Mastriano S, Wang N, Lu J: microRNA Expression Profiling: Technologies, Insights, and Prospects. Adv Exp Med Biol. 2015. PMID: 26663195
- Xiang Y, Cheng J, Wang D, Hu X, Xie Y, Stitham J, Atteya G, Du J, Tang WH, Lee SH, Leslie K, Spollett G, Liu Z, Herzog E, Herzog RI, Lu J, Martin KA, Hwa J: Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor. Blood. 2015 May 28; 2015 Mar 26. PMID: 25814526
- Moskwa P, Zinn PO, Choi YE, Shukla SA, Fendler W, Chen CC, Lu J, Golub TR, Hjelmeland A, Chowdhury D: A functional screen identifies miRs that induce radioresistance in glioblastomas. Mol Cancer Res. 2014 Dec; 2014 Sep 25. PMID: 25256711
- Lu J, Cheng L, Lau KC, Tyo E, Luo X, Wen J, Miller D, Assary RS, Wang HH, Redfern P, Wu H, Park JB, Sun YK, Vajda S, Amine K, Curtiss LA: Effect of the size-selective silver clusters on lithium peroxide morphology in lithium-oxygen batteries. Nat Commun. 2014 Sep 12; 2014 Sep 12. PMID: 25215517
- Liu C, Rennie WA, Carmack CS, Kanoria S, Cheng J, Lu J, Ding Y: Effects of genetic variations on microRNA: target interactions. Nucleic Acids Res. 2014 Sep; 2014 Jul 31. PMID: 25081214
- Rennie W, Liu C, Carmack CS, Wolenc A, Kanoria S, Lu J, Long D, Ding Y: STarMir: a web server for prediction of microRNA binding sites. Nucleic Acids Res. 2014 Jul; 2014 May 6. PMID: 24803672
- Guo S, Zi X, Schulz VP, Cheng J, Zhong M, Koochaki SH, Megyola CM, Pan X, Heydari K, Weissman SM, Gallagher PG, Krause DS, Fan R, Lu J: Nonstochastic reprogramming from a privileged somatic cell state. Cell. 2014 Feb 13; 2014 Jan 30. PMID: 24486105
- Di Stefano B, Sardina JL, van Oevelen C, Collombet S, Kallin EM, Vicent GP, Lu J, Thieffry D, Beato M, Graf T: C/EBPα poises B cells for rapid reprogramming into induced pluripotent stem cells. Nature. 2014 Feb 13; 2013 Dec 15. PMID: 24336202
- Guo Y, Mastriano S, Lu J: A high-throughput microRNA expression profiling system. Methods Mol Biol. 2014. PMID: 25030917
- Cheng J, Guo S, Chen S, Mastriano SJ, Liu C, D'Alessio AC, Hysolli E, Guo Y, Yao H, Megyola CM, Li D, Liu J, Pan W, Roden CA, Zhou XL, Heydari K, Chen J, Park IH, Ding Y, Zhang Y, Lu J: An extensive network of TET2-targeting MicroRNAs regulates malignant hematopoiesis. Cell Rep. 2013 Oct 31; 2013 Oct 10. PMID: 24120864
- Megyola CM, Gao Y, Teixeira AM, Cheng J, Heydari K, Cheng EC, Nottoli T, Krause DS, Lu J, Guo S: Dynamic migration and cell-cell interactions of early reprogramming revealed by high-resolution time-lapse imaging. Stem Cells. 2013 May. PMID: 23335078
- Stahlhut C, Suárez Y, Lu J, Mishima Y, Giraldez AJ: miR-1 and miR-206 regulate angiogenesis by modulating VegfA expression in zebrafish. Development. 2012 Dec 1. PMID: 23132244
- Adams BD, Guo S, Bai H, Guo Y, Megyola CM, Cheng J, Heydari K, Xiao C, Reddy EP, Lu J: An in vivo functional screen uncovers miR-150-mediated regulation of hematopoietic injury response. Cell Rep. 2012 Oct 25; 2012 Oct 19. PMID: 23084747
- Guo S, Bai H, Megyola CM, Halene S, Krause DS, Scadden DT, Lu J: Complex oncogene dependence in microRNA-125a-induced myeloproliferative neoplasms. Proc Natl Acad Sci U S A. 2012 Oct 9; 2012 Sep 24. PMID: 23012470