1 Introduction An Extensive Review of the History of Gene Transcription Research and Timeline of Milestones in this Field.
2 Chromatin Functions to Define Cell State

Required Readings

Weintraub, H., and M. Groudine. “Chromosomal Subunits in Active Genes have an Altered Conformation.” Science 193, no. 4256 (1976): 848-856.

Meshorer, E., D. Yellajoshula, E. George, P. J. Scambler, D. T. Brown, and T. Misteli. “Hyperdynamic Plasticity of Chromatin Proteins in Pluripotent Embryonic Stem Cells.” Developmental Cell 10, no. 1 (2006): 105-116.

The first paper describes how differential packaging of the same gene in different cell types or states either allows or restricts access of the gene to the transcriptional machinery, providing a mechanism for differential gene regulation. The second paper discusses how chromatin in embryonic stem cells may be particularly dynamic, permitting transitions into many possible cell fates.

Suggested Readings / Bonus Materials

Zwaka, T. P. “Breathing Chromatin in Pluripotent Stem Cells.” Developmental Cell 10, no. 1 (2006): 1-2.

Supplemental Data for Meshorer, et al. Developmental Cell 10: 105-116.

Kirschner, M. “In Memory of Harold Weintraub.” Molecular Biology of the Cell 6, no. 7 (1995): 757-758. (PDF)

Axel, Richard, and Tom Maniatis. “Harold Weintraub (1945-1995).Cell 81, no. 3 (1995): 317-318. 

3 Chromatin Structure and Discovery of Chromatin Modifying Enzymes

Required Readings

Brownell, J. E., J. Zhou, T. Ranalli, R. Kobayashi, D. G. Edmondson, S. Y. Roth, and C. D. Allis. “Tetrahymena Histone Acetyltransferase A: A Homolog to Yeast Gcn5p Linking Histone Acetylation to Gene Activation.Cell 84, no. 6 (1996): 843-851.

Taunton, J., C. A. Hassig, and S. L. Schreiber. “A Mammalian Histone Deacetylase Related to the Yeast Transcriptional Regulator Rpd3p.” Science 272, no. 5260 (1996): 408-411.

These papers describe the initial isolation and transcriptional association of histone acetyltransferases (HATs) and histone deacetylases (HDACs). The results described here directed attention to histone modifications as critical regulators of transcription.

Suggested Readings / Bonus Materials

Pennisi, Elizabeth. “Molecular Biology: Opening the Way to Gene Activity.” Science 275, no. 5297 (1997): 155-157.

———. “Champion of Chromatin: Alan Wolffe (1959-2001).” Science 293, no. 5532 (2001): 1065.

Marks, Paul A., Richard A. Rifkind, Victoria M. Richon, Ronald Breslow, Thomas Miller, and William K. Kelly. “Histone Deacetylases and Cancer: Causes and Therapies.” Nature Reviews: Cancer 1, no. 3 (2001): 194-202.

Downey, Philip. “Profile of C. David Allis.” Proceedings of the National Academy of Sciences 103, no. 17 (2006): 6425-6427. (PDF)

4 Methylation and the Emergence of the “Histone Code”

Required Readings

Lachner, M., D. O’Carroll, S. Rea, K. Mechtler, and T. Jenuwein. “Methylation of Histone H3 Lysine 9 Creates a Binding Site for HP1 Proteins.” Nature 410, no. 6824 (2001): 116-120.

Wysocka, J., T. Swigut, T. A. Milne, Y. Dou, X. Zhang, A. L. Burlingame, R. G. Roeder, A. H. Brivanlou, and C. D. Allis. “WDR5 Associates with Histone H3 Methylated at K4 and Is Essential for H3 K4 Methylation and Vertebrate Development.” Cell 121, no. 6 (2005): 859-872.

These papers describe the interactions of the “histone code” where a histone modification results in recruitment of a transcriptional effector. Importantly, they describe the how histone modifications communicate with important developmental regulators.

Suggested Readings / Bonus Materials

Jenuwein, Thomas and C. David Allis. “Translating the Histone Code.” Science 293, no. 5532 (2001): 1074-1080.

Fischle, Wolfgang, Yanming Wang, and C. David Allis. “Histone and Chromatin Cross-Talk.” Current Opinion in Cell Biology 15, no. 2 (2003/4): 172-183.

5 Heritable Gene Expression via Epigenetic Modification of Chromatin

Required Readings

Nielsen, S. J., R. Schneider, U. M. Bauer, A. J. Bannister, A. Morrison, D. O’Carroll, and R. Firestein, et al. “Rb Targets Histone H3 Methylation and HP1 to Promoters.” Nature 412, no. 6846 (2001): 561-565.

Ayyanathan, K., M. S. Lechner, P. Bell, G. G. Maul, D. C. Schultz, Y. Yamada, K. Tanaka, K. Torigoe, and F. J. Rauscher 3rd. “Regulated Recruitment of HP1 to a Euchromatic Gene Induces Mitotically Heritable, Epigenetic Gene Silencing: A Mammalian Cell Culture Model of Gene Variegation.” Genes & Development 17, no. 15 (2003): 1855-1869. (PDF)

These papers describe how chromatin modifications can set up a stable transcriptional state that is heritable from mother to daughter cell. Also, they show how this chromatin modification system can be used by important cellular pathways such as the retinoblastoma (Rb) tumor suppressor pathway that governs cell growth.

Suggested Readings / Bonus Materials

Jones, Peter A., and Robert Martienssen. “A Blueprint for a Human Epigenome Project: The AACR Human Epigenome Workshop.” Cancer Research 65, no. 24 (2005): 11241-11246. (PDF)

Lund, Anders H., and Maarten van Lohuizen. “Epigenetics and Cancer.” Genes & Development 18, no. 19 (2004): 2315-2335. (PDF)

Fahrner, Jill A., and Stephen B. Baylin. “Heterochromatin: Stable and Unstable Invasions at Home and Abroad.” Genes & Development 17, no. 15 (2003): 1805-1812. (PDF)

Ringrose, Leonie, and Renato Paro. “Gene Regulation: Cycling Silence.” Nature 412, no. 6846 (2001): 493-494.

6 Regulators of Pluripotency and Differentiation of Stem Cells

Required Readings

Chambers, I., D. Colby, M. Robertson, J. Nichols, S. Lee, S. Tweedie, and A. Smith. “Functional Expression Cloning of Nanog, a Pluripotency Sustaining Factor in Embryonic Stem Cells.” Cell 113, no. 5 (2003): 643-655.

Wichterle, H., I. Lieberam, J. A. Porter, and T. M. Jessell. “Directed Differentiation of Embryonic Stem Cells into Motor Neurons.” Cell 110, no. 3 (2002): 385-397.

The first paper describes the identification of the homeodomain protein Nanog as one of the key regulators maintaining pluripotency in embryonic stem cells. The second details efforts to drive embryonic stem cells into the neuronal lineage.

Suggested Readings / Bonus Materials

Cavaleri, Fatima, and Hans R. Schöler. “Nanog: A New Recruit to the Embryonic Stem Cell Orchestra.” Cell 113, no. 5 (2003): 551-552.

Solter, Davor, and John Gearhart. “BIOMEDICINE:Enhanced: Putting Stem Cells to Work.” Science 283, no. 5407 (1999): 1468-1470.

Boyer, Laurie A., Divya Mathur, and Rudolf Jaenisch. “Molecular Control of Pluripotency.” Current Opinion in Genetics & Development 16, no. 5 (2006): 455-462.

Department of Health and Human Services. “Rebuilding the Nervous System with Stem Cells.” Chapter 8 in Stem Cells: Scientific Progress and Future Research Directions. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, June 2001.

For Stem Cell Experts, Hopes Are Longterm. Human Trials Still Years Away in Effort to Cure Paralysis.” San Francisco Chronicle, September 26, 2005.

7 Tour of Novartis Institute for Biomedical Research Laboratories  
8 Regulation of Early Development by Polycomb Proteins

Required Readings

Cao, R., L. Wang, H. Wang, L. Xia, H. Erdjument-Bromage, P. Tempst, R. S. Jones, and Y. Zhang. “Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing.” Science 298, no. 5595 (2002): 1039-1043.

Bracken, A. P., N. Dietrich, D. Pasini, K. H. Hansen, and K. Helin. “Genome-Wide Mapping of Polycomb Target Genes Unravels their Roles in Cell Fate Transitions.” Genes & Development 20, no. 9 (2006): 1123-1136. (PDF)

These papers show how the H3K27-polycomb system sets up developmental states to allow for appropriate differentiation.

Suggested Readings / Bonus Materials

Scientists Solve a Mystery of Cell Determination.” San Francisco Chronicle, April 30, 2006.

Sparmann, Anke, and Maarten van Lohuizen. “Polycomb Silencers Control Cell Fate, Development and Cancer.” Nature Reviews: Cancer 6, no. 11 (2006): 846-856.

Polycomb Information from the Interactive Fly Resource

9 Master Regulators of Differentiation: The Story of MyoD

Required Readings

Davis, R. L., H. Weintraub, and A. B. Lassar. “Expression of a Single Transfected cDNA Converts Fibroblasts to Myoblasts.” Cell 51, no. 6 (1987): 987-1000.

Blais, A., M. Tsikitis, D. Acosta-Alvear, R. Sharan, Y. Kluger, and B. D. Dynlacht. “An Initial Blueprint for Myogenic Differentiation.” Genes & Development 19, no. 5 (2005): 553-569. (PDF)

The first paper describes the strategy used to isolate MyoD, the classic ‘master regulatory gene’ that has the ability to transdifferentiate a variety of cell and tissue types into muscle. The second is a more recent paper detailing the regulatory circuitry that drives muscle differentiation.

Suggested Readings / Bonus Materials

Tapscott, Stephen J. “The Circuitry of a Master Switch: MyoD and the Regulation of Skeletal Muscle Gene Transcription.” Development 132, no. 12 (2005): 2685-2695. (PDF)

Weintraub, Harold, Robert Davis, Stephen Tapscott, Matthew Thayer, Michael Krause, Robert Benezra, and T. Keith Blackwell, et al. “The myoD Gene Family: Nodal Point during Specification of the Muscle Cell Lineage.” Science 251, no. 4995 (1991): 761-766.

Weintraub, Harold, Stephen J. Tapscott, Robert L. Davis, Mathew J. Thayer, Mohammed A. Adam, Andrew B. Lassar, and A. Dusty Miller. “Activation of Muscle-Specific Genes in Pigment, Nerve, Fat, Liver, and Fibroblast Cell Lines by Forced Expression of MyoD.” Proceedings of the National Academy of Sciences 86, no. 14 (1989): 5434-5438. (PDF - 1.6 MB)

10 Chromatin Modifications During Development

Required Readings

Grigoryev, S. A., T. Nikitina, J. R. Pehrson, P. B. Singh, and C. L. Woodcock. “Dynamic Relocation of Epigenetic Chromatin Markers Reveals an Active Role of Constitutive Heterochromatin in the Transition from Proliferation to Quiescence.” Journal of Cell Science 117, no. Pt 25 (2004): 6153-6162.

Kanellopoulou, C., S. A. Muljo, A. L. Kung, S. Ganesan, R. Drapkin, T. Jenuwein, D. M. Livingston, and K. Rajewsky. “Dicer-Deficient Mouse Embryonic Stem Cells Are Defective in Differentiation and Centromeric Silencing.” Genes & Development 19, no. 4 (2005): 489-501.

The first paper investigates the chromatin changes that occur as cells terminally differentiate from a proliferative to quiescent state. The second paper uses genetics to define a possible role for non-coding RNAs in the silencing of mammalian centromeres.

11 Transdifferentiation, Dedifferentiation, and the Adoption of Alternate Cell Fates

Required Readings

Odelberg, S. J., A. Kollhoff, and M. T. Keating. “Dedifferentiation of Mammalian Myotubes Induced by msx1.” Cell 103, no. 7 (2000): 1099-1109.

Takahashi, K., and S. Yamanaka. “Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors.” Cell 126, no. 4 (2006): 663-676.

The first paper suggests that the same factor that plays a role in limb regeneration in newts may be capable of returning mammalian muscle fibers to an undifferentiated state. The second paper claims to define a cocktail of transcription factors that confer pluripotency upon differentiated adult cells.

Suggested Readings / Bonus Materials

Rodolfa, Kit T., and Kevin Eggan. “A Transcriptional Logic for Nuclear Reprogramming.” Cell 126, no. 4 (2006): 652-655.

Hughes, Simon M. “Muscle Development: Reversal of the Differentiated State.” Current Biology 11, no. 6 (2001): R237-R239.

Supplemental Materials for Takahashi and Yamanaka Paper

Hochedlinger, Konrad, and Rudolf Jaenisch. “Nuclear Reprogramming and Pluripotency.” Nature 441, no. 7097 (2006): 1061-1067.

Echeverri, Karen, and Elly M. Tanaka. “Mechanisms of Muscle Dedifferentiation during Regeneration.” Seminars in Cell & Developmental Biology 13, no. 5 (2002): 353-360.

12 When Regulators Go Bad: Misregulation of Chromatin Modifiers in Cancer

Required Readings

Grignani, F., S. De Matteis, C. Nervi, L. Tomassoni, V. Gelmetti, M. Cioce, and M. Fanelli, et al. “Fusion Proteins of the Retinoic Acid Receptor-Alpha Recruit Histone Deacetylase in Promyelocytic Leukaemia.” Nature 391, no. 6669 (1998): 815-818.

Okada, Y., Q. Feng, Y. Lin, Q. Jiang, Y. Li, V. M. Coffield, L. Su, G. Xu, and Y. Zhang. “HDOT1L Links Histone Methylation to Leukemogenesis.” Cell 121, no. 2 (April 22, 2005): 167-178.

These papers show how normal chromatin regulators can be hijacked by chromosomal translocations to impose transcriptional programs that are not healthy for the organism. Specifically, misregulation of these integral chromatin modifiers results in blood cancer.

13 Oral Presentation of Research Proposals  
Course Info
As Taught In
Fall 2006
Learning Resource Types
assignment Presentation Assignments