The identification of the gene regulatory network that controls the formation of xylem — the major component of wood — opens up new avenues for manipulating plant biomass. See Article p.571

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An Arabidopsis gene regulatory network for secondary cell wall synthesis

Taylor-Teeples, M.; Lin, L.; de Lucas, M.; Turco, G.; Toal, T. W.; Gaudinier, A.; Young, N. F.; Trabucco, G. M.; Veling, M. T.; Lamothe, R.; Handakumbura, P. P.; Xiong, G.; Wang, C.; Corwin, J.; Tsoukalas, A.; Zhang, L.; Ware, D.; Pauly, M.; Kliebenstein, D. J.; Dehesh, K.; Tagkopoulos, I.; Breton, G.; Pruneda-Paz, J. L.; Ahnert, S. E.; Kay, S. A.; Hazen, S. P.; Brady, S. M.

2014 Nature

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Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex

Konermann, Silvana; Brigham, Mark D.; Trevino, Alexandro E.; Joung, Julia; Abudayyeh, Omar O.; Barcena, Clea; Hsu, Patrick D.; Habib, Naomi; Gootenberg, Jonathan S.; Nishimasu, Hiroshi; Nureki, Osamu; Zhang, Feng

2014 Nature

doi: 10.1038/nature14136

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Resolving the complexity of the human genome using single-molecule sequencing

Chaisson, Mark J. P.; Huddleston, John; Dennis, Megan Y.; Sudmant, Peter H.; Malig, Maika; Hormozdiari, Fereydoun; Antonacci, Francesca; Surti, Urvashi; Sandstrom, Richard; Boitano, Matthew; Landolin, Jane M.; Stamatoyannopoulos, John A.; Hunkapiller, Michael W.; Korlach, Jonas;

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Interception of host angiogenic signalling limits mycobacterial growth

Oehlers, Stefan H.; Cronan, Mark R.; Scott, Ninecia R.; Thomas, Monica I.; Okuda, Kazuhide S.; Walton, Eric M.; Beerman, Rebecca W.; Crosier, Philip S.; Tobin, David M.

2014 Nature

doi: 10.1038/nature13967pmid: 25470057

Using a model of tuberculosis in zebrafish, granuloma formation is shown to coincide with hypoxia and angiogenesis; furthermore, the pharmacological inhibition of the pro-angiogenic VEGF pathway reduces infection burden, suggesting a possible treatment strategy in patients with the disease.

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Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury

Vaughan, Andrew E.; Brumwell, Alexis N.; Xi, Ying; Gotts, Jeffrey E.; Brownfield, Doug G.; Treutlein, Barbara; Tan, Kevin; Tan, Victor; Liu, Feng Chun; Looney, Mark R.; Matthay, Michael A.; Rock, Jason R.; Chapman, Harold A.

2014 Nature

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IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo

Venkatanarayan, Avinashnarayan; Raulji, Payal; Norton, William; Chakravarti, Deepavali; Coarfa, Cristian; Su, Xiaohua; Sandur, Santosh K.; Ramirez, Marc S.; Lee, Jaehuk; Kingsley, Charles V.; Sananikone, Eliot F.; Rajapakshe, Kimal; Naff, Katherine; Parker-Thornburg, Jan;

journal article

LitStream Collection

The mitotic checkpoint complex binds a second CDC20 to inhibit active APC/C

Izawa, Daisuke; Pines, Jonathon

2014 Nature

doi: 10.1038/nature13911pmid: 25383541

By binding and inhibiting a second CDC20 molecule, the mitotic checkpoint complex can convert a local ‘wait’ signal from unattached kinetochores to inhibit the anaphase promoting complex/cyclosome throughout the cell and avoid premature cell division.

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LitStream Collection

Uncovering the polymerase-induced cytotoxicity of an oxidized nucleotide

Freudenthal, Bret D.; Beard, William A.; Perera, Lalith; Shock, David D.; Kim, Taejin; Schlick, Tamar; Wilson, Samuel H.

2014 Nature

doi: 10.1038/nature13886pmid: 25409153

Time--β bound to substrate DNA as it inserts 8-oxo-dGTP opposite either cytosine or adenine.

journal article

LitStream Collection

Structural insight into autoinhibition and histone H3-induced activation of DNMT3A

Guo, Xue; Wang, Ling; Li, Jie; Ding, Zhanyu; Xiao, Jianxiong; Yin, Xiaotong; He, Shuang; Shi, Pan; Dong, Liping; Li, Guohong; Tian, Changlin; Wang, Jiawei; Cong, Yao; Xu, Yanhui

2014 Nature

doi: 10.1038/nature13899

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doi: 10.1038/nature14099pmid: 25533953

The plant cell wall is an important factor for determining cell shape, function and response to the environment. Secondary cell walls, such as those found in xylem, are composed of cellulose, hemicelluloses and lignin and account for the bulk of plant biomass. The coordination between transcriptional regulation of synthesis for each polymer is complex and vital to cell function. A regulatory hierarchy of developmental switches has been proposed, although the full complement of regulators remains unknown. Here we present a protein–DNA network between Arabidopsis thaliana transcription factors and secondary cell wall metabolic genes with gene expression regulated by a series of feed-forward loops. This model allowed us to develop and validate new hypotheses about secondary wall gene regulation under abiotic stress. Distinct stresses are able to perturb targeted genes to potentially promote functional adaptation. These interactions will serve as a foundation for understanding the regulation of a complex, integral plant component.

pmid:

25494202

Systematic interrogation of gene function requires the ability to perturb gene expression in a robust and generalizable manner. Here we describe structure-guided engineering of a CRISPR-Cas9 complex to mediate efficient transcriptional activation at endogenous genomic loci. We used these engineered Cas9 activation complexes to investigate single-guide RNA (sgRNA) targeting rules for effective transcriptional activation, to demonstrate multiplexed activation of ten genes simultaneously, and to upregulate long intergenic non-coding RNA (lincRNA) transcripts. We also synthesized a library consisting of 70,290 guides targeting all human RefSeq coding isoforms to screen for genes that, upon activation, confer resistance to a BRAF inhibitor. The top hits included genes previously shown to be able to confer resistance, and novel candidates were validated using individual sgRNA and complementary DNA overexpression. A gene expression signature based on the top screening hits correlated with markers of BRAF inhibitor resistance in cell lines and patient-derived samples. These results collectively demonstrate the potential of Cas9-based activators as a powerful genetic perturbation technology.

Eichler, Evan E.

2014 Nature

doi: 10.1038/nature13907pmid: 25383537

Single-molecule, real-time DNA sequencing is used to analyse a haploid human genome (CHM1), thus closing or extending more than half of the remaining 164 euchromatic gaps in the human genome; the complete sequences of euchromatic structural variants (including inversions, complex insertions and tandem repeats) are resolved at the base-pair level, suggesting that a greater complexity of the human genome can now be accessed.

doi: 10.1038/nature14112pmid: 25533958

Lineage-tracing experiments identify a rare, undifferentiated population of quiescent cells in the mouse distal lung that are activated through a Notch signalling pathway to repair the epithelium after bleomycin- or influenza-mediated injury; inappropriate Notch signalling may be a major contributor to failed regeneration within the lungs of patients with chronic lung disease.

Bankson, James A.;

Tsai, Kenneth Y.;

Gunaratne, Preethi H.;

Flores, Elsa R.

2014 Nature

doi: 10.1038/nature13910pmid: 25409149

p53 is often mutated or lost in cancer; here inactivation of ΔNp63 and ΔNp73 in the absence of p53 is shown to result in metabolic reprogramming and tumour regression via activation of IAPP (islet amyloid polypeptide or amylin), and IAPP-based anti-diabetes therapeutic strategies show potential for the treatment of p53-deficient and mutant tumours.

pmid:

25383530

A working model for histone H3-induced dynamic regulation of the de novo DNA methyltransferase.