Molecular Biology Faculty
Carl Icahn Lab, 144
Lab (609) 258-3839
1. General Lab Description
The Lieb lab is committed to understanding how information is encoded, maintained, and dynamically utilized in living eukaryotic genomes. To this end, the projects in the laboratory seek to understand relationships between DNA packaging (chromatin), the targeting of regulatory proteins such as transcription factors to specific genomic targets, and the mechanism by which these regulatory proteins exert their influence on DNA-dependent enzymes. We also aim to identify and characterize areas of the genome that serve to regulate chromosomal functions, including transcription, DNA replication and repair, recombination, and chromosome segregation.
To address these questions, we use three biological systems: (1) S. cerevisiae to address basic molecular mechanisms; (2) C. elegans to test the importance of those mechanisms in a simple multicellular organism and to serve as a "stepping stone" to bridge yeast and human studies; and (3) cell lines and clinical samples to directly interrogate relevance to human development and disease. We also work with Drosophila in collaboration with other laboratories.
The integration of these systems in my lab permits us to quickly bring concepts discovered in models to medical relevance. For example, we developed FAIRE, a method to detect regions of "open" chromatin. FAIRE was initially discovered in yeast, and we have since implemented this technology in human cells as part of our participation in the ENCODE project. We have now extended this work to clinical tissue samples to directly interrogate the role of regulatory element function in human development and disease.
2. Some specific projects ongoing in the lab:
(1) Uniting disparate fields to explore transcription factor binding dynamics
Genomic processes, including transcription and the binding of transcriptional regulators, are inherently dynamic. However, most of what we know about the mechanisms underlying transcriptional regulation is derived from static assays like footprinting or Chromatin Immunoprecipitation (ChIP), in which information about dynamics is lost. To overcome this limitation we combine the comprehensiveness and high spatial resolution of genomic, population-based methods like ChIP-seq with the high temporal resolution of single-cell, microscopy-based methods like fluorescence recovery after photobleaching (FRAP).
(2) Highly parallel functional characterization of human regulatory elements
One of the most effective means of discovering human transcriptional regulatory elements is through the identification of "open chromatin" using methods like DNaseI hypersensitivity or FAIRE. In collaboration with the Segal lab in Israel, we are developing a high throughput assay to simultaneously detect and test the function of tens of thousands of human regulatory elements in a single experiment, and test the effect of natural human sequence variation within functional elements.
(3) Profiling RNA and chromatin components of the early C. elegans embryo
The invariant, asymmetric cell divisions in early C. elegans development provide an ideal model system to study how cell fate determinants are inherited and segregated. We study the chromatin and RNA components in sperm and oocyte, and then combine blastomere-specific isolation with ultra-low input RNA-seq protocols to map RNA inheritance and transcriptional activity after the first cell division. These data allow us to understand how molecular components are inherited, and define the mechanisms required for asymmetric RNA segregation to directly test its biological significance.
Other areas of active research in our lab are focused on the following problems:
(4) the link between genetic variation in human regulatory elements and alterations in gene expression; (5) the role of the nuclear envelope and nuclear pores in genome organization and transcriptional regulation; and (6) the characterization and functional implications of somatic nucleotide variation in normal human tissues.
Grohman JK, Gorelick RJ, Lickwar, CR, Lieb JD, Bower BD, Znosko BM, Weeks KM, A guanosine-centric mechanism for RNA chaperone function. Science. 2013 Apr 12; 340(6129):190. PMID: 23470731
Rohner S, Kalck V, Wang X, Ikegami K, Lieb JD, Gasser SM, Meister P., Promoter - and RNA polymerase II-dependent hsp-16 gene association with nuclear pores in Caenorhabditis elegans., J Cell Biol. 2013 Mar 4;200(5):589-604. PMID: 23460676
Vielle A, Lang J, Dong Y, Ercan S, Kotwaliwale C, Rechtsteiner A, Appert A, Chen QB, Dose A, Egelhofer T, Kimura H, Stempor P, Dernburg A, Lieb JD, Strome S, Ahringer J., H4K20me1 Contributes to Downregulation of X-Linked Genes for C. elegans Dosage Compensation. PLoS Genetics. 2012 Sep;8(9):e1002933. PMID: 23028348
Landt SG, Marinov GK, Kundaje A, Kheradpour P, Pauli F, Batzoglou S, Bernstein BE, Bickel P, Brown JB, Cayting P, Chen Y, Desalvo G, Epstein C, Fisher-Aylor KI, Euskirchen G, Gerstein M, Gertz J, Hartemink AJ, Hoffman MM, Iyer VR, Jung YL, Karmakar S, Kellis M, Kharchenko PV, Li Q, Liu T, Liu XS, Ma L, Milosavljevic A, Myers RM, Park PJ, Pazin MJ, Perry MD, Raha D, Reddy TE, Rozowsky J, Shoresh N, Sidow A, Slattery M, Stamatoyannopoulos JA, Tolstorukov MY, White KP, Xi S, Farnham PJ, Lieb JD, Wold BJ, Snyder M., ChIP-seq guidelines and practices of the ENCODE and modENCODE consortia. Genome Research. 2012 Sep;22(9):1813-31. PMID: 22955991
Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, Haugen E, Sheffield NC, Stergachis AB, Wang H, Vernot B, Garg K, John S, Sandstrom R, Bates D, Boatman L, Canfield TK, Diegel M, Dunn D, Ebersol AK, Frum T, Giste E, Johnson AK, Johnson EM, Kutyavin T, Lajoie B, Lee BK, Lee K, London D, Lotakis D, Neph S, Neri F, Nguyen ED, Qu H, Reynolds AP, Roach V, Safi A, Sanchez ME, Sanyal A, Shafer A, Simon JM, Song L, Vong S, Weaver M, Yan Y, Zhang Z, Zhang Z, Lenhard B, Tewari M, Dorschner MO, Hansen RS, Navas PA, Stamatoyannopoulos G, Iyer VR, Lieb JD, Sunyaev SR, Akey JM, Sabo PJ, Kaul R, Furey TS, Dekker J, Crawford GE, Stamatoyannopoulos JA., The accessible chromatin landscape of the human genome., Nature. 2012 Sep 6;489(7414):75-82. PMID: 22955617
ENCODE Project Consortium (453 authors), An integrated encyclopedia of DNA elements in the human genome. Nature. 2012 Sep 6;489(7414):57-74. PMID: 22955616
Gossett, AG, Lieb JD, In vivo effects of histone H3 depletion on nucleosome occupancy and position in Saccharomyces cerevisiae, PLoS Genetics. 2012 Jun;8(6):e1002771. PMID: 22737086
Chen Y, Negre N, Li Q, Mieczkowska JO, Slatttery M, Liu T, Zhang Y, Kim TK, He HH, Zieba J, Ruan Y, Bickel PJ, Myers RM, Wold BJ, White KP*, Lieb JD*, Liu XS* *co-corresponding, Systematic evaluation of factors influencing ChIP-seq fidelity., Nature Methods. 2012 Apr 22. PMID: 22522655
Lickwar CR, Mueller F, Hanlon SE, McNally JG, Lieb JD., Genome-wide protein-DNA binding dynamics suggest a molecular clutch for transcription factor function. Nature. 2012. Apr 11; 484(7393):251-5 PMID:22498630.
Gassmann R, Rechtsteiner A, Yuen KW, Muroyama A, Egelhofer T, Gaydos L, Barron F, Maddox P, Essex A, Monen J, Ercan S, Lieb JD, Oegema K, Strome S, Desai A., An Inverse Relationship to Germline Transcription Defines the C. elegans Holocentromere in Progeny. Nature. 2012. Apr 8; 484 (7395):4534-7 PMID: 22495302
Lee BK, Bhinge AA, Battenhouse A, McDaniell RM, Liu Z, Song L, Ni Y, Birney E, Lieb JD, Furey TS, Crawford GE, Iyer VR., Cell-type specific and combinatorial usage of diverse transcription factors revealed by genome-wide binding studies in multiple human cells. Genome Research. 2012 Jan;22(1):9-24. PMID: 22090374
Patel M, Simon JM, Iglesia MD, Wu SB, McFadden AW, Lieb JD, Davis IJ., Tumor-specific retargeting of an oncogenic transcription factor chimera results in dysregulation of chromatin and transcription. Genome Research. 2011 Nov 15. PMID: 22086061
Deng X, Hiatt JB, Nguyen DK, Ercan S, Sturgill D, Hillier LW, Schlesinger F, Davis CA, Reinke VJ, Gingeras TR, Shendure J, Waterston RH, Oliver B*, Lieb JD*, Disteche CM*. *co-corresponding, Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster. Nature Genetics. 2011 Oct 23. doi: 10.1038/ng.948. PMID: 22019781
Mansisidor AR, Cecere G, Hoersch S, Jensen MB, Kawli T, Kennedy LM, Chavez V, Tan MW, Lieb JD, Grishok A., A conserved PHD finger protein and endogenous RNAi modulate insulin signaling in Caenorhabditis elegans. PLoS Genetics. 2011 Sep;7(9):e1002299. PMID: 21980302
Rashid N, Giresi PG, Ibrahim JG, Sun W*, Lieb JD*. ZINBA integrates local covariates with DNA-seq data to identify broad and narrow regions of enrichment, even within amplified genomic regions., Genome Biology. 2011 Jul 25;12(7):R67. PMID: 21787385
Song L, Zhang Z, Grasfeder LL, Boyle AP, Giresi PG, Lee BK, Sheffield NC, Gräf S, Huss M, Keefe D, Liu Z, London D, McDaniell RM, Shibata Y, Showers KA, Simon JM, Vales T, Wang T, Winter D, Zhang Z, Clarke ND, Birney E*, Iyer VR*, Crawford GE*, Lieb JD*, Furey TS*, Open chromatin defined by DNaseI and FAIRE identifies regulatory elements that shape cell-type identity. Genome Research. 2011 Jul 12. PMID: 21750106
Hanlon SE, Rizzo JM, Tatomer DC, Lieb JD*, Buck MJ*, The Stress Response Factors Yap6, Cin5, Phd1, and Skn7 Direct Targeting of the Conserved Co-Repressor Tup1-Ssn6., PLoS ONE. 2011. 6(4): e19060. doi:10.1371/journal.pone.0019060
Liu T, Rechtsteiner A, Egelhofer TA, Vielle A, Latorre I, Cheung MS, Ercan S, Ikegami K, Jensen M, Kolasinska-Zwierz P, Rosenbaum H, Shin H, Taing S, Takasaki T, Iniguez AL, Desai A, Dernburg AF, Kimura H, Lieb JD, Ahringer J, Strome S, Liu XS., Broad chromosomal domains of histone modification patterns in C. elegans Genome Research. 2011 Feb;21(2):227-36. PMID: 21177964 PMCID: PMC3032926
Ercan S*, Lubling Y, Segal E*, Lieb JD., High nucleosome occupancy is encoded at X-linked gene promoters in C. elegans. Genome Research. 2011 Feb;21(2):237-44. PMID: 21177966 PMCID: PMC3032927
Egelhofer TA, Minoda A, Klugman S, Lee K, Kolasinska-Zwierz P, Alekseyenko AA, Cheung MS, Day DS, Gadel S, Gorchakov AA, Gu T, Kharchenko PV, Kuan S, Latorre I, Linder-Basso D, Luu Y, Ngo Q, Perry M, Rechtsteiner A, Riddle NC, Schwartz YB, Shanower GA, Vielle A, Ahringer J, Elgin SC, Kuroda MI, Pirrotta V, Ren B, Strome S, Park PJ*, Karpen GH*, Hawkins RD*, Lieb JD*., An assessment of histone-modification antibody quality. Nature Structural and Molecular Biology. 2011 Jan;18(1):91-3. PMID: 21131980 PMCID: PMC3017233
Ikegami K, Egelhofer TA, Strome S, Lieb JD., C. elegans chromosome arms are anchored to the nuclear membrane via discontinuous association with LEM-2. Genome Biology. 2010;11(12):R120. PMID: 21176223 PMCID: PMC3046480
Gerstein MB*, [100 others], Strome S*, Gunsalus KC*, Micklem G*, X. Liu S*, Reinke V*, Kim SK*, HillierLW*, Henikoff S*, Piano F*, Snyder M*, Stein L*, Lieb JD*, Waterston RH*.,Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project. Science. 2010 Dec 24;330(6012):1775-87. PMID: 21177976
Burns C, Stajich JE, Rechtsteiner A, Casselton L, Hanlon SE, Wilke SK, Savytskyy OP, Gathman AC, Lilly WW, Lieb JD, Zolan ME, Pukkila PJ., Analysis of the basidiomycete Coprinopsis cinerea reveals conservation of the core meiotic expression program over half a billion years of evolution. PLoS Genetics. 2010 Sep 23;6(9). e1001135. PMID: 20885784 PMCID: PMC2944786
Rechtsteiner A, Ercan S, Takasaki T, Phippen TM, Egelhofer TA, Wang W, Kimura H, Lieb JD, Strome S., The histone H3K36 methyltransferase MES-4 acts epigenetically to transmit the memory of germline gene expression to progeny. PLoS Genetics. 2010 Sep 2;6(9). e1001091. PMID: 20824077 PMCID: 2932692
McDaniell R, Lee BK, Song L, ..., Lieb JD, ..., Birney E. (2010) Heritable individual-specific and allele-specific chromatin signatures in humans. Science. 328: 235-9. Pubmed
He HH, Meyer C, Shin H, ..., Lieb JD, ..., Liu XS. (2010) Nucleosome dynamics define transcriptional enhancers. Nature Genet. 42: 343-7. Pubmed
Tillo D, Kaplan N, Moore IK, ..., Lieb JD ..., Hughes TR. (2010) High nucleosome occupancy is encoded at human regulatory sequences. PLoS ONE. 5: e9129. Pubmed
Gaulton KJ, Nammo T, Pasquali L, ..., Lieb JD*, Ferrer J*. (2010) A map of open chromatin in human pancreatic islets. Nature Genet. 42: 255-9. Pubmed
Ercan S, Dick LL, Lieb JD (2009) The C. elegans dosage compensation complex propagates dynamically and independently of X-chromosome sequence. Curr Biol. 19: 1777-87. Pubmed