Let a hundred flowers bloom: the role of context dependence in creating phenotypic diversity following targeted therapy
AuthorsLee, Michael J.
UMass Chan AffiliationsProgram in Systems Biology
MetadataShow full item record
AbstractUsing a newly developed computational platform, COSPER, Litvin et al. (2015) identify context-dependent interactions between MEK and interferon signaling that underlie sensitivity and resistance to MEK inhibition in melanoma.
SourceMol Cell. 2015 Mar 5;57(5):763-4. doi: 10.1016/j.molcel.2015.02.030. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/49941
Related ResourcesLink to Article in PubMed
Showing items related by title, author, creator and subject.
Mapping and analysis of Caenorhabditis elegans transcription factor sequence specificitiesNarasimhan, Kamesh; Lambert, Samuel A.; Yang, Ally; Riddell, Jeremy; Mnaimneh, Sanie; Zheng, Hong; Albu, Mihai; Najafabadi, Hamed S.; Reece-Hoyes, John S.; Fuxman Bass, Juan; et al. (2015-04-23)Caenorhabditis elegans is a powerful model for studying gene regulation, as it has a compact genome and a wealth of genomic tools. However, identification of regulatory elements has been limited, as DNA-binding motifs are known for only 71 of the estimated 763 sequence-specific transcription factors (TFs). To address this problem, we performed protein binding microarray experiments on representatives of canonical TF families in C. elegans, obtaining motifs for 129 TFs. Additionally, we predict motifs for many TFs that have DNA-binding domains similar to those already characterized, increasing coverage of binding specificities to 292 C. elegans TFs (~40%). These data highlight the diversification of binding motifs for the nuclear hormone receptor and C2H2 zinc finger families, and reveal unexpected diversity of motifs for T-box and DM families. Motif enrichment in promoters of functionally related genes is consistent with known biology, and also identifies putative regulatory roles for unstudied TFs.
The genome-wide multi-layered architecture of chromosome pairing in early Drosophila embryosErceg, Jelena; AlHaj Abed, Jumana; Goloborodko, Anton; Lajoie, Bryan R.; Fudenberg, Geoffrey; Abdennur, Nezar; Imakaev, Maxim; McCole, Ruth B.; Nguyen, Son C.; Saylor, Wren; et al. (2019-10-03)Genome organization involves cis and trans chromosomal interactions, both implicated in gene regulation, development, and disease. Here, we focus on trans interactions in Drosophila, where homologous chromosomes are paired in somatic cells from embryogenesis through adulthood. We first address long-standing questions regarding the structure of embryonic homolog pairing and, to this end, develop a haplotype-resolved Hi-C approach to minimize homolog misassignment and thus robustly distinguish trans-homolog from cis contacts. This computational approach, which we call Ohm, reveals pairing to be surprisingly structured genome-wide, with trans-homolog domains, compartments, and interaction peaks, many coinciding with analogous cis features. We also find a significant genome-wide correlation between pairing, transcription during zygotic genome activation, and binding of the pioneer factor Zelda. Our findings reveal a complex, highly structured organization underlying homolog pairing, first discovered a century ago in Drosophila. Finally, we demonstrate the versatility of our haplotype-resolved approach by applying it to mammalian embryos.
Determination of ubiquitin fitness landscapes under different chemical stresses in a classroom settingMavor, David; Roscoe, Benjamin P.; Bolon, Daniel N.; Fraser, James S. (2016-04-25)Ubiquitin is essential for eukaryotic life and varies in only 3 amino acid positions between yeast and humans. However, recent deep sequencing studies indicate that ubiquitin is highly tolerant to single mutations. We hypothesized that this tolerance would be reduced by chemically induced physiologic perturbations. To test this hypothesis, a class of first year UCSF graduate students employed deep mutational scanning to determine the fitness landscape of all possible single residue mutations in the presence of five different small molecule perturbations. These perturbations uncover 'shared sensitized positions' localized to areas around the hydrophobic patch and the C-terminus. In addition, we identified perturbation specific effects such as a sensitization of His68 in HU and a tolerance to mutation at Lys63 in DTT. Our data show how chemical stresses can reduce buffering effects in the ubiquitin proteasome system. Finally, this study demonstrates the potential of lab-based interdisciplinary graduate curriculum.