1.  Splicing in humans is supposedly much more prevalent than in other organisms with similar genome sizes, leading to more types of proteins.  Read a group of papers on both sides of this assertion and see if you believe this, or just write about an aspect of splicing of human genes.  Starter resource:  Kwan, T, Benovoy, D, Dias, C, Gurd, S, Provencher, C, Beaulieu, P, Hudson, T, Sladek, R, and Majoewski, J.  Genome-wide analysis of transcript isoform variation in humans.  Nature Genetics Jan 2008, online release in advance of publication, 7 pp (find on PubMed).

2.       X-chromosome inactivation has been mysterious for years;  it was thought that DNA methylation was the first signal, then it was thought that the RNA product of the Xist gene was the first signal.  Now more complexities, including interaction of Xist with the product of an overlapping gene ( Tsix, that runs in the opposite direction), regulation by transcription, and regulation by the protein CTCF have come into the picture.  Evaluate the currently proposed mechanism(s).  Possibly useful reference: Hernandez-Munoz, I., et al., Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase.  Proc Natl Acad Sci USA 102:7635-7640 (2005). 

3.       BRCA1 and BRCA2 are genes that have been associated with breast cancer.  They have been shown to have a role in DNA repair, but don’t focus on that.  Instead, examine evidence that one or both of them has a role in regulation of transcription and/or chromatin remodeling.  Here is a possibly useful reference:   Bochar et al., BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell 102:257-265 (2000).  (note: this is one of the papers we read and discuss, so it cannot be included in your five, but can get you started).

4.       Interactions between RNAi and chromatin structure, such as that based on the alternative histone H2AZ,  have been found in several organisms.  Consider delimiting the topic by choosing one organism and perhaps even one gene to focus on in your paper.  Possibly useful references:  Creyghton, M, Markoulaki, S, Levy, S, Levine, S, Hanna, J, Lodato, M, Sha, K, Young, R, Jaenisch, R, and Boyer, L.  H2AZ is enriched at polycomb complex target genes in ES cells and is necessary for lineage commitment.  Cell 135:649- 661(2008), Pal-Bhadra, M., et al., Heterochromatic silencing and HP1 localization in Drosophila are dependent on the RNAi machinery, Science 202:669-672 (2004).

5.       Epigenetic changes in cancer.  Epigenetic changes such as DNA methylation or methylation and/or acetylation of histones can have a big impact in carcinogenesis.  There are way too many papers on these topics, so if you choose something in this area, delimit it to one mechanism and perhaps one gene or one organism or some other useful category.  Possibly useful reference: review article: Gronbaek, K, Hother, C and Peter A Jones, Epigenetic changes in cancer, APMIS 115:1039-1059 (2007).  

6.       DNA methylation in cancer.  One specific area from 5 above.  Possibly useful references: Zhang, Q., Wang, H, Marzer, M, Raghunath,PN, Nagasawa, T and Waski, M.  STAT3-and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes.  Proc Natl Acad Sci USA 102:6948-53 (2005), Linhart**, H, Lin, H, Yamada, Y, Moran, E, Steine, E, Goldhale, S, Lo, G, Cantu, E, Ehrich, M, He, T, Meissner, A, and Jaenisch, R  Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing.  Gene & Devel. 21:3110-3122 (2007).

7.       Imprinting is a mechanism, other than in X-inactivation, that causes only one allele of a gene to be expressed.  Either the maternal or the paternal version is turned off during gametogenesis.  Here is a possibly useful review article: Allshire and Bickmore, Pausing for thought on the boundaries of imprinting.  Cell 102:705-708 (2000).

8.       Histone code.  The specifically modified sites in the histones near a gene appear to be a code that regulates packaging and expression.  Evaluate current evidence of the specific marks associated with different states or the regulation of how domains are ‘chosen’ to be opened or closed.  Possibly useful references:  review article… Feinberg, AP, Phenotypic plasticity and the epigenetics of human disease.  Nature 447: 433-440  (May, 2007).  Figure 1 is especially useful. 

9.       9.  Transcription factors: is there a discernable pattern for genome-wide binding of major transcription factors?         Possibly useful resource: Iyer et al, Genomic binding sites of the yeast cell-cycle transcription factors SBF and     MBF.  Nature 409:533-538 (2001) (found at http://genome-www.stanford.edu/chromatinip/sbfmdf.pdf ).

10.   Are transcription factors the most important prime movers in eukaryotic regulation or are they restrained by chromatin?  Here is a possibly useful review article resource on the side of the TFs: Kadonaga, JT, Regulation of RNA Polymerase II transcription by sequence-specific DNA binding factors. Cell 116:247-257.

11.   The so-called Id proteins are inactive partners that can bind to transcription factors that act as dimers and prevent them from binding to DNA sites.  Delve into the recent findings about these proteins, for example in stem cells or cancer.  Possibly useful classical reference: Barone, MV, Pepperkok, R, Peverali, F, and Philipson, L.  Id proteins control growth induction in mammalian cells.  Proc Natl Acad Sci USA 91:4985-4988 (1994). 

12.   Reprogramming of body cells to form pluripotent cells similar to stem cells.  Look for recent papers by Jaenisch, by Yamanaka, and by James Thomson on reprogramming or iPS (induced pluripotent stem) cells. 

13.   Plant cell epigenetic  controls.  DNA methylation, RNAi, and histone code functions have often been clearer and easier to demonstrate in plants than in animals.  Focus on one of these regulatory mechanisms in plants.  Possibly useful reference:  Epigenetic Programming via Histone Methylation at WRKY53 controls Leaf Senescence in Arabidopsis thaliana.  Ay N, Irmler K, Fischer A, Uhlemann R, Reuter G, Humbeck K. Plant J. 2008 Dec 26. [Epub ahead of print]  PMID: 19143996 [PubMed - as supplied by publisher] Related Articles

14.   Stem cell gene expression.  A very competitive and hot field is attempting to identify those genes whose expression predicts pluripotency, the unique quality of stem cells.  Possibly useful reference: Assou S, Cerecedo D, Tondeur S, Pantesco V, Hovatta O, Klein B, Hamamah S, De Vos J. A gene expression signature shared by human mature oocytes and embryonic stem cells.BMC Genomics. 2009 Jan 8;10(1):10.

15.   Transcription factors in development.  Many papers are coming out on the roles of specific transcription factors in the development of particular cell and tissue types.  Choose one you’re interested in and focus on it for your paper.  Or compare two different cell or tissue types in terms of the TFs that regulate them.  Look for TFs that are important in the shape of fingers or fins.  Or maybe ones that influence a particular neural crest cell for neurons or pigment cells.  What's the regulatory basis of a zebra's stripes or five versus six toed cats?

16.   Chemists have found that a focus on a particular TF can be productive in working against carcinogenesis.  Find some cases of this type of drug design and compare strategies and effectiveness.  Possibly useful reference:  Timofeeva, O, Gaponenko, V, Lockett, S, Tarasov, S, Jiang, S, Michejda, C, Perantoni, A, and Tarasova, N.  Rationally Designed Inhibitors Identify STAT3 N-Domain as a Promising Anticancer Drug Target.  ACS Chemical Biology 2:799-804.

17.  Look for how regulatory changes can make an organism more adapted to its environment.  Start off with the papers and news articles in the last two sessions of the course. (but remember you can't use those papers since we will discuss them in class, you'll need to find papers they refer to or look for papers that cite them).

18.  New understandings of non-coding RNAs in gene regulation.  How can miRNA molecules regulate gene up and down regulation?  Evidently there are several different mechanisms in play.  Look at the miRNA papers we covered in the first section of the class (but don't use them for one of the five because we will discuss them in class).

19.  Genetic diseases related to imprinting of genes.  Several human genetic diseases appear to be caused by defective imprinting or problems with imprinting.  Choose one such disease and find several mechanisms that seem to operate for it.