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