Bioinformatics, Developmental Biology, Gene Discovery, Regeneration, Stem Cells, Transcription Factors, Tumor Suppressor Genes
Biophysics and Systems Pharmacology [BSP], Developmental and Stem Cell Biology [DSCB]
BA, Johns Hopkins University
PhD, Massachusetts Institute of Technology
, Whitehead Institute for Biomedical Research
The focus of my research is to understand the molecular and cellular nature of the undifferentiated stem cell "states", and how such states are altered during a change in cell fate. The underlying rationale for our studies is that the complement of gene-products and their inter-relationships that exist in stem cells accounts for their remarkable abilities to balance self-renewal and differentiation decision processes. We study both adult and embryonic stem (ES) cells, primarily from the mouse, but also from the human. As a first step, we have comprehensively identified most, if not all gene-products that are expressed in highly purified hematopoietic stem cell (HSC). We performed similar analyses in mouse ES cells. Such molecular "signatures" provide parts-lists that are available to the stem cells. The challenge has been to functionally address the roles that these molecules play in mediating the biological properties of HSC and ES cells. Further, we would like to understand how these molecular components are "wired" into regulatory signaling and transcriptional networks. To explore these issues we have utilized a number of global gene-expression perturbation technologies, such as inhibitory short hairpin RNA (shRNA). We have successfully down regulated the expression levels of candidate regulatory molecules in both HSC and ES cells. A number of these play crucial regulatory roles in processes such as self-renewal, proliferation, and differentiation. We have further developed strategies that allow the analyses of cell-fate change dynamics at multiple biochemical and molecular levels in response to defined and precisely controlled changes in the expression levels of key regulatory molecules. These strategies have provided the first in-depth view of how a cell-fate decision actually occurs at the transcriptional, post-transcriptional, translational, and post-translational levels. An important aspect of our overall efforts is computational and quantitative analyses. We anticipate that our approach will yield a systems biology level description and understanding of stem cell decision processes. This in turn, will have profound implications in future efforts focused on applying basic stem cell research in translational as well as clinical contexts.
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Lee DF, Su J, Kim HS, Chang B, Papatsenko D, Zhao R, Yuan Y, Gingold J, Xia W, Darr H, Mirzayans R, Hung MC, Schaniel C, Lemischka IR. Modeling familial cancer with induced pluripotent stem cells. Cell 2015 Apr; 161(2).
Papatsenko D, Lemischka IR. NetExplore: a web server for modeling small network motifs. Bioinformatics (Oxford, England) 2015 Jan;.
Gingold JA, Fidalgo M, Guallar D, Lau Z, Sun Z, Zhou H, Faiola F, Huang X, Lee DF, Waghray A, Schaniel C, Felsenfeld DP, Lemischka IR, Wang J. A genome-wide RNAi screen identifies opposing functions of Snai1 and Snai2 on the Nanog dependency in reprogramming. Molecular cell 2014 Oct; 56(1).
Xu H, Ang YS, Sevilla A, Lemischka IR, Ma'ayan A. Construction and validation of a regulatory network for pluripotency and self-renewal of mouse embryonic stem cells. PLoS computational biology 2014 Aug; 10(8).
Kim HS, Bernitz JM, Lee DF, Lemischka IR. Genomic editing tools to model human diseases with isogenic pluripotent stem cells. Stem cells and development 2014 Nov; 23(22).
Pereira CF, Lemischka IR, Moore K. 'From blood to blood': de-differentiation of hematopoietic progenitors to stem cells. The EMBO journal 2014 Jul; 33(14).
Pereira CF, Lemischka IR, Moore K. There will be blood. Cell cycle (Georgetown, Tex.) 2014; 13(3).
Kuo HP, Wang Z, Lee DF, Iwasaki M, Duque-Afonso J, Wong SH, Lin CH, Figueroa ME, Su J, Lemischka IR, Cleary ML. Epigenetic roles of MLL oncoproteins are dependent on NF-κB. Cancer cell 2013 Oct; 24(4).
Zhang H, Nieves JL, Fraser ST, Isern J, Douvaras P, Papatsenko D, D'Souza SL, Lemischka IR, Dyer MA, Baron MH. Expression of podocalyxin separates the hematopoietic and vascular potentials of mouse embryonic stem cell-derived mesoderm. Stem cells (Dayton, Ohio) 2014 Jan; 32(1).
MacArthur BD, Lemischka IR. Statistical mechanics of pluripotency. Cell 2013 Aug; 154(3).
Zhang YS, Sevilla A, Wan LQ, Lemischka IR, Vunjak-Novakovic G. Patterning pluripotency in embryonic stem cells. Stem cells (Dayton, Ohio) 2013 Sep; 31(9).
Xu H, Baroukh C, Dannenfelser R, Chen EY, Tan CM, Kou Y, Kim YE, Lemischka IR, Ma'ayan A. ESCAPE: database for integrating high-content published data collected from human and mouse embryonic stem cells. Database : the journal of biological databases and curation 2013; 2013.
Pereira CF, Chang B, Qiu J, Niu X, Papatsenko D, Hendry CE, Clark NR, Nomura-Kitabayashi A, Kovacic JC, Ma'ayan A, Schaniel C, Lemischka IR, Moore K. Induction of a hemogenic program in mouse fibroblasts. Cell stem cell 2013 Aug; 13(2).
Binda O, Sevilla A, LeRoy G, Lemischka IR, Garcia BA, Richard S. SETD6 monomethylates H2AZ on lysine 7 and is required for the maintenance of embryonic stem cell self-renewal. Epigenetics : official journal of the DNA Methylation Society 2013 Feb; 8(2).
MacArthur BD, Sevilla A, Lenz M, Müller FJ, Schuldt BM, Schuppert AA, Ridden SJ, Stumpf PS, Fidalgo M, Ma'ayan A, Wang J, Lemischka IR. Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity. Nature cell biology 2012 Nov; 14(11).
Fidalgo M, Faiola F, Pereira CF, Ding J, Saunders A, Gingold J, Schaniel C, Lemischka IR, Silva JC, Wang J. Zfp281 mediates Nanog autorepression through recruitment of the NuRD complex and inhibits somatic cell reprogramming. Proceedings of the National Academy of Sciences of the United States of America 2012 Oct; 109(40).
Pereira CF, Lemischka IR, Moore K. Reprogramming cell fates: insights from combinatorial approaches. Annals of the New York Academy of Sciences 2012 Aug; 1266.
Lee DF, Su J, Ang YS, Carvajal-Vergara X, Mulero-Navarro S, Pereira CF, Gingold J, Wang HL, Zhao R, Sevilla A, Darr H, Williamson AJ, Chang B, Niu X, Aguilo F, Flores ER, Sher YP, Hung MC, Whetton AD, Gelb BD, Moore KA, Snoeck HW, Ma'ayan A, Schaniel C, Lemischka IR. Regulation of embryonic and induced pluripotency by aurora kinase-p53 signaling. Cell stem cell 2012 Aug; 11(2).
Lee DF, Su J, Sevilla A, Gingold J, Schaniel C, Lemischka IR. Combining competition assays with genetic complementation strategies to dissect mouse embryonic stem cell self-renewal and pluripotency. Nature protocols 2012 Apr; 7(4).
Ling J, Kang Y, Zhao R, Xia Q, Lee DF, Chang Z, Li J, Peng B, Fleming JB, Wang H, Liu J, Lemischka IR, Hung MC, Chiao PJ. KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer cell 2012 Jan; 21(1).
Schaniel C, Sirabella D, Qiu J, Niu X, Lemischka IR, Moore KA. Wnt-inhibitory factor 1 dysregulation of the bone marrow niche exhausts hematopoietic stem cells. Blood 2011 Sep; 118(9).
Ang YS, Gaspar-Maia A, Lemischka IR, Bernstein E. Stem cells and reprogramming: breaking the epigenetic barrier?. Trends in pharmacological sciences 2011 Jul; 32(7).
Tsai SY, Bouwman BA, Ang YS, Kim SJ, Lee DF, Lemischka IR, Rendl M. Single transcription factor reprogramming of hair follicle dermal papilla cells to induced pluripotent stem cells. Stem cells (Dayton, Ohio) 2011 Jun; 29(6).
Ang YS, Tsai SY, Lee DF, Monk J, Su J, Ratnakumar K, Ding J, Ge Y, Darr H, Chang B, Wang J, Rendl M, Bernstein E, Schaniel C, Lemischka IR. Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network. Cell 2011 Apr; 145(2).
Josowitz R, Carvajal-Vergara X, Lemischka IR, Gelb BD. Induced pluripotent stem cell-derived cardiomyocytes as models for genetic cardiovascular disorders. Current opinion in cardiology 2011 May; 26(3).
Green MD, Chen A, Nostro MC, d'Souza SL, Schaniel C, Lemischka IR, Gouon-Evans V, Keller G, Snoeck HW. Generation of anterior foregut endoderm from human embryonic and induced pluripotent stem cells. Nature biotechnology 2011 Mar; 29(3).
Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P, Lemischka IR, Zhou BY, Snoeck HW. Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood 2011 May; 117(19).
Honda H, Takubo K, Oda H, Kosaki K, Tazaki T, Yamasaki N, Miyazaki K, Moore KA, Honda Z, Suda T, Lemischka IR. Hemp, an mbt domain-containing protein, plays essential roles in hematopoietic stem cell function and skeletal formation. Proceedings of the National Academy of Sciences of the United States of America 2011 Feb; 108(6).
Markowetz F, Mulder KW, Airoldi EM, Lemischka IR, Troyanskaya OG. Mapping dynamic histone acetylation patterns to gene expression in nanog-depleted murine embryonic stem cells. PLoS computational biology 2010; 6(12).
Xu H, Lemischka IR, Ma'ayan A. SVM classifier to predict genes important for self-renewal and pluripotency of mouse embryonic stem cells. BMC systems biology 2010; 4.
Xu H, Schaniel C, Lemischka IR, Ma'ayan A. Toward a complete in silico, multi-layered embryonic stem cell regulatory network. Wiley interdisciplinary reviews. Systems biology and medicine; 2(6).
Schaniel C, Lee DF, Lemischka IR. Exploration of self-renewal and pluripotency in ES cells using RNAi. Methods in enzymology 2010; 477.
Carvajal-Vergara X, Sevilla A, D'Souza SL, Ang YS, Schaniel C, Lee DF, Yang L, Kaplan AD, Adler ED, Rozov R, Ge Y, Cohen N, Edelmann LJ, Chang B, Waghray A, Su J, Pardo S, Lichtenbelt KD, Tartaglia M, Gelb BD, Lemischka IR. Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature 2010 Jun; 465(7299).
Lemischka IR. Hooking up with Oct4. Cell stem cell 2010 Apr; 6(4).
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