Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens.
AuthorsBehan FM, Iorio F, Picco G, Gonçalves E, Beaver CM, Migliardi G, Santos R, Rao Y, Sassi F, Pinnelli M, Ansari R, Harper S, Jackson DA, McRae R, Pooley R, Wilkinson P, van der Meer D, Dow D, Buser-Doepner C, Bertotti A, Trusolino L, Stronach EA, Saez-Rodriguez J, Yusa K, Garnett MJ
JournalNature
PubMed ID30971826
'Functional genomics approaches can overcome limitations-such as the lack of identification of robust targets and poor clinical efficacy-that hamper cancer drug development. Here we performed genome-scale CRISPR-Cas9 screens in 324 human cancer cell lines from 30 cancer types and developed a data-driven framework to prioritize candidates for cancer therapeutics. We integrated cell ... More
ZFP30 promotes adipogenesis through the KAP1-mediated activation of a retrotransposon-derived Pparg2 enhancer.
AuthorsChen W, Schwalie PC, Pankevich EV, Gubelmann C, Raghav SK, Dainese R, Cassano M, Imbeault M, Jang SM, Russeil J, Delessa T, Duc J, Trono D, Wolfrum C, Deplancke B
JournalNat Commun
PubMed ID31000713
'Krüppel-associated box zinc finger proteins (KZFPs) constitute the largest family of mammalian transcription factors, but most remain completely uncharacterized. While initially proposed to primarily repress transposable elements, recent reports have revealed that KFZPs contribute to a wide variety of other biological processes. Using murine and human in vitro and in ... More
Genome-wide mapping reveals that deoxyuridine is enriched in the human centromeric DNA.
AuthorsShu X, Liu M, Lu Z, Zhu C, Meng H, Huang S, Zhang X, Yi C
JournalNat Chem Biol
PubMed ID29785056
'Uracil in DNA can be generated by cytosine deamination or dUMP misincorporation; however, its distribution in the human genome is poorly understood. Here we present a selective labeling and pull-down technology for genome-wide uracil profiling and identify thousands of uracil peaks in three different human cell lines. Surprisingly, uracil is ... More
CRISPR-Cas9 epigenome editing enables high-throughput screening for functional regulatory elements in the human genome.
AuthorsKlann TS, Black JB, Chellappan M, Safi A, Song L, Hilton IB, Crawford GE, Reddy TE, Gersbach CA
JournalNat Biotechnol
PubMed ID28369033
Large genome-mapping consortia and thousands of genome-wide association studies have identified non-protein-coding elements in the genome as having a central role in various biological processes. However, decoding the functions of the millions of putative regulatory elements discovered in these studies remains challenging. CRISPR-Cas9-based epigenome editing technologies have enabled precise perturbation ... More
Optogenetic control of kinetochore function.
AuthorsZhang H, Aonbangkhen C, Tarasovetc EV, Ballister ER, Chenoweth DM, Lampson MA
JournalNat Chem Biol
PubMed ID28805800
Kinetochores act as hubs for multiple activities during cell division, including microtubule interactions and spindle checkpoint signaling. Each kinetochore can act autonomously, and activities change rapidly as proteins are recruited to, or removed from, kinetochores. Understanding this dynamic system requires tools that can manipulate kinetochores on biologically relevant temporal and ... More
Enhancer connectome in primary human cells identifies target genes of disease-associated DNA elements.
AuthorsMumbach MR, Satpathy AT, Boyle EA, Dai C, Gowen BG, Cho SW, Nguyen ML, Rubin AJ, Granja JM, Kazane KR, Wei Y, Nguyen T, Greenside PG, Corces MR, Tycko J, Simeonov DR, Suliman N, Li R, Xu J, Flynn RA, Kundaje A, Khavari PA, Marson A, Corn JE, Quertermous T, Greenleaf WJ, Chang HY
JournalNat Genet
PubMed ID28945252
The challenge of linking intergenic mutations to target genes has limited molecular understanding of human diseases. Here we show that H3K27ac HiChIP generates high-resolution contact maps of active enhancers and target genes in rare primary human T cell subtypes and coronary artery smooth muscle cells. Differentiation of naive T cells ... More
Massively parallel Cas13 screens reveal principles for guide RNA design.
AuthorsWessels HH, Méndez-Mancilla A, Guo X, Legut M, Daniloski Z, Sanjana NE
JournalNat Biotechnol
PubMed ID32518401
Type VI CRISPR enzymes are RNA-targeting proteins with nuclease activity that enable specific and robust target gene knockdown without altering the genome. To define rules for the design of Cas13d guide RNAs (gRNAs), we conducted massively parallel screens targeting messenger RNAs (mRNAs) of a green fluorescent protein transgene, and CD46, ... More