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Genes & Development

Frédéric Gachon, Jake Yeung, Felix Naef
Mammalian physiology resonates with the daily changes in the external environment, allowing processes such as rest-activity cycles, metabolism, and body temperature to synchronize with daily changes in the surroundings. Studies have identified the molecular underpinnings of robust oscillations in gene expression occurring over the 24-h day, but how acute or chronic perturbations modulate gene expression rhythms, physiology, and behavior is still relatively unknown. In this issue of Genes & Development , Hong and colleagues (pp...
November 1, 2018: Genes & Development
Yulong Su, Carl Pelz, Tao Huang, Kristof Torkenczy, Xiaoyan Wang, Allison Cherry, Colin J Daniel, Juan Liang, Xiaolin Nan, Mu-Shui Dai, Andrew Adey, Soren Impey, Rosalie C Sears
The transcription factor MYC (also c-Myc) induces histone modification, chromatin remodeling, and the release of paused RNA polymerase to broadly regulate transcription. MYC is subject to a series of post-translational modifications that affect its stability and oncogenic activity, but how these control MYC's function on the genome is largely unknown. Recent work demonstrates an intimate connection between nuclear compartmentalization and gene regulation. Here, we report that Ser62 phosphorylation and PIN1-mediated isomerization of MYC dynamically regulate the spatial distribution of MYC in the nucleus, promoting its association with the inner basket of the nuclear pore in response to proliferative signals, where it recruits the histone acetyltransferase GCN5 to bind and regulate local gene acetylation and expression...
November 1, 2018: Genes & Development
Yang Liu, Tao Wang, Yon Ju Ji, Kenji Johnson, Honghe Liu, Kaitlin Johnson, Scott Bailey, Yongwon Suk, Yu-Ning Lu, Mingming Liu, Jiou Wang
Cells undergo metabolic adaptation during environmental changes by using evolutionarily conserved stress response programs. This metabolic homeostasis is exquisitely regulated, and its imbalance could underlie human pathological conditions. We report here that C9orf72, which is linked to the most common forms of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is a key regulator of lipid metabolism under stress. Loss of C9orf72 leads to an overactivation of starvation-induced lipid metabolism that is mediated by dysregulated autophagic digestion of lipids and increased de novo fatty acid synthesis...
November 1, 2018: Genes & Development
Brandon J Aubrey, Ana Janic, Yunshun Chen, Catherine Chang, Elizabeth C Lieschke, Sarah T Diepstraten, Andrew J Kueh, Jonathan P Bernardini, Grant Dewson, Lorraine A O'Reilly, Lachlan Whitehead, Anne K Voss, Gordon K Smyth, Andreas Strasser, Gemma L Kelly
Mutations in Trp53 , prevalent in human cancer, are reported to drive tumorigenesis through dominant-negative effects (DNEs) over wild-type TRP53 function as well as neomorphic gain-of-function (GOF) activity. We show that five TRP53 mutants do not accelerate lymphomagenesis on a TRP53-deficient background but strongly synergize with c-MYC overexpression in a manner that distinguishes the hot spot Trp53 mutations. RNA sequencing revealed that the mutant TRP53 DNE does not globally repress wild-type TRP53 function but disproportionately impacts a subset of wild-type TRP53 target genes...
November 1, 2018: Genes & Development
Hee-Kyung Hong, Eleonore Maury, Kathryn Moynihan Ramsey, Mark Perelis, Biliana Marcheva, Chiaki Omura, Yumiko Kobayashi, Denis C Guttridge, Grant D Barish, Joseph Bass
The mammalian circadian clock is encoded by an autoregulatory transcription feedback loop that drives rhythmic behavior and gene expression in the brain and peripheral tissues. Transcriptomic analyses indicate cell type-specific effects of circadian cycles on rhythmic physiology, although how clock cycles respond to environmental stimuli remains incompletely understood. Here, we show that activation of the inducible transcription factor NF-κB in response to inflammatory stimuli leads to marked inhibition of clock repressors, including the Period , Cryptochrome , and Rev-erb genes, within the negative limb...
November 1, 2018: Genes & Development
Claudio Cantù, Anastasia Felker, Dario Zimmerli, Karin D Prummel, Elena M Cabello, Elena Chiavacci, Kevin M Méndez-Acevedo, Lucia Kirchgeorg, Sibylle Burger, Jorge Ripoll, Tomas Valenta, George Hausmann, Nathalie Vilain, Michel Aguet, Alexa Burger, Daniela Panáková, Konrad Basler, Christian Mosimann
Bcl9 and Pygopus (Pygo) are obligate Wnt/β-catenin cofactors in Drosophila , yet their contribution to Wnt signaling during vertebrate development remains unresolved. Combining zebrafish and mouse genetics, we document a conserved, β-catenin-associated function for BCL9 and Pygo proteins during vertebrate heart development. Disrupting the β-catenin-BCL9-Pygo complex results in a broadly maintained canonical Wnt response yet perturbs heart development and proper expression of key cardiac regulators. Our work highlights BCL9 and Pygo as selective β-catenin cofactors in a subset of canonical Wnt responses during vertebrate development...
November 1, 2018: Genes & Development
Kushal K Banerjee, Madhurima Saxena, Namit Kumar, Lei Chen, Alessia Cavazza, Natalie H Toke, Nicholas K O'Neill, Shariq Madha, Unmesh Jadhav, Michael P Verzi, Ramesh A Shivdasani
After acquiring competence for selected cell fates, embryonic primordia may remain plastic for variable periods before tissue identity is irrevocably determined (commitment). We investigated the chromatin basis for these developmental milestones in mouse endoderm, a tissue with recognizable rostro-caudal patterning and transcription factor (TF)-dependent interim plasticity. Foregut-specific enhancers are as accessible and active in early midgut as in foregut endoderm, and intestinal enhancers and identity are established only after ectopic cis -regulatory elements are decommissioned...
November 1, 2018: Genes & Development
Francesco Vuolo, Daniel Kierzkowski, Adam Runions, Mohsen Hajheidari, Remco A Mentink, Mainak Das Gupta, Zhongjuan Zhang, Daniela Vlad, Yi Wang, Ales Pecinka, Xiangchao Gan, Angela Hay, Peter Huijser, Miltos Tsiantis
How the interplay between cell- and tissue-level processes produces correctly proportioned organs is a key problem in biology. In plants, the relative size of leaves compared with their lateral appendages, called stipules, varies tremendously throughout development and evolution, yet relevant mechanisms remain unknown. Here we use genetics, live imaging, and modeling to show that in Arabidopsis leaves , the LATE MERISTEM IDENTITY1 (LMI1) homeodomain protein regulates stipule proportions via an endoreduplication-dependent trade-off that limits tissue size despite increasing cell growth...
November 1, 2018: Genes & Development
Ayala Tovy, Adam Spiro, Ryan McCarthy, Zohar Shipony, Yael Aylon, Kendra Allton, Elena Ainbinder, Noa Furth, Amos Tanay, Michelle Barton, Moshe Oren
No abstract text is available yet for this article.
October 1, 2018: Genes & Development
Chantal Priesnitz, Thomas Becker
Mitochondria contain their own genome that encodes for a small number of proteins, while the vast majority of mitochondrial proteins is produced on cytosolic ribosomes. The formation of respiratory chain complexes depends on the coordinated biogenesis of mitochondrially encoded and nuclear-encoded subunits. In this review, we describe pathways that adjust mitochondrial protein synthesis and import of nuclear-encoded subunits to the assembly of respiratory chain complexes. Furthermore, we outline how defects in protein import into mitochondria affect nuclear gene expression to maintain protein homeostasis under physiological and stress conditions...
October 1, 2018: Genes & Development
Hugo Gonzalez, Catharina Hagerling, Zena Werb
The presence of inflammatory immune cells in human tumors raises a fundamental question in oncology: How do cancer cells avoid the destruction by immune attack? In principle, tumor development can be controlled by cytotoxic innate and adaptive immune cells; however, as the tumor develops from neoplastic tissue to clinically detectable tumors, cancer cells evolve different mechanisms that mimic peripheral immune tolerance in order to avoid tumoricidal attack. Here, we provide an update of recent accomplishments, unifying concepts, and future challenges to study tumor-associated immune cells, with an emphasis on metastatic carcinomas...
October 1, 2018: Genes & Development
M Carmen Lafita-Navarro, Min Kim, Nofit Borenstein-Auerbach, Niranjan Venkateswaran, Yi-Heng Hao, Roshni Ray, Thomas Brabletz, Pier Paolo Scaglioni, Jerry W Shay, Maralice Conacci-Sorrell
MYC enhances protein synthesis by regulating genes involved in ribosome biogenesis and protein translation. Here, we show that MYC-induced protein translation is mediated by the transcription factor aryl hydrocarbon receptor (AHR), which is induced by MYC in colonic cells. AHR promotes protein synthesis by activating the transcription of genes required for ribosome biogenesis and protein translation, including OGFOD1 and NOLC1. Using surface sensing of translation (SUnSET) to measure global protein translation, we found that silencing AHR or its targets diminishes protein synthesis...
October 1, 2018: Genes & Development
Peng Hu, Jian Liu, Juanjuan Zhao, Benjamin J Wilkins, Katherine Lupino, Hao Wu, Liming Pei
A fundamental challenge in understanding cardiac biology and disease is that the remarkable heterogeneity in cell type composition and functional states have not been well characterized at single-cell resolution in maturing and diseased mammalian hearts. Massively parallel single-nucleus RNA sequencing (snRNA-seq) has emerged as a powerful tool to address these questions by interrogating the transcriptome of tens of thousands of nuclei isolated from fresh or frozen tissues. snRNA-seq overcomes the technical challenge of isolating intact single cells from complex tissues, including the maturing mammalian hearts; reduces biased recovery of easily dissociated cell types; and minimizes aberrant gene expression during the whole-cell dissociation...
October 1, 2018: Genes & Development
Adriana B Arongaus, Song Chen, Marie Pireyre, Nina Glöckner, Vinicius C Galvão, Andreas Albert, J Barbro Winkler, Christian Fankhauser, Klaus Harter, Roman Ulm
Plants have evolved complex photoreceptor-controlled mechanisms to sense and respond to seasonal changes in day length. This ability allows plants to optimally time the transition from vegetative growth to flowering. UV-B is an important part intrinsic to sunlight; however, whether and how it affects photoperiodic flowering has remained elusive. Here, we report that, in the presence of UV-B, genetic mutation of REPRESSOR OF UV-B PHOTOMORPHOGENESIS 2 ( RUP2 ) renders the facultative long day plant Arabidopsis thaliana a day-neutral plant and that this phenotype is dependent on the UV RESISTANCE LOCUS 8 (UVR8) UV-B photoreceptor...
October 1, 2018: Genes & Development
Kohji Hizume, Shizuko Endo, Sachiko Muramatsu, Takehiko Kobayashi, Hiroyuki Araki
The proper pausing of replication forks at barriers on chromosomes is important for genome integrity. However, the detailed mechanism underlying this process has not been well elucidated. Here, we successfully reconstituted fork-pausing reactions from purified yeast proteins on templates that had binding sites for the LacI, LexA, and/or Fob1 proteins; the forks paused specifically at the protein-bound sites. Moreover, although the replicative helicase Cdc45-Mcm2-7-GINS (CMG) complex alone unwound the protein-bound templates, the unwinding of the LacI-bound site was impeded by the presence of a main leading strand DNA polymerase: polymerase ε (Polε)...
October 1, 2018: Genes & Development
Takeo Horie, Ryoko Horie, Kai Chen, Chen Cao, Masashi Nakagawa, Takehiro G Kusakabe, Noriyuki Satoh, Yasunori Sasakura, Michael Levine
The CNS of the protovertebrate Ciona intestinalis contains a single cluster of dopaminergic (DA) neurons, the coronet cells, which have been likened to the hypothalamus of vertebrates. Whole-embryo single-cell RNA sequencing (RNA-seq) assays identified Ptf1a as the most strongly expressed cell-specific transcription factor (TF) in DA/coronet cells. Knockdown of Ptf1a activity results in their loss, while misexpression results in the appearance of supernumerary DA/coronet cells. Photoreceptor cells and ependymal cells are the most susceptible to transformation, and both cell types express high levels of Meis Coexpression of both Ptf1a and Meis caused the wholesale transformation of the entire CNS into DA/coronet cells...
October 1, 2018: Genes & Development
Yao Wan, Anita K Hopper
The mitochondrial cytoplasmic surface serves as a processing site for numerous RNAs from budding yeast to metazoans. We report that budding yeast mitochondrial outer membrane (MOM) proteins that are subunits of the translocase of the outer mitochondrial membrane (Tom70 and Tom 22) and sorting and assembly machinery (Sam37) are required for efficient pretransfer RNA (pre-tRNA) splicing. Defective pre-tRNA splicing in MOM mutants is due not to loss of respiratory metabolism but instead inefficient targeting/tethering of tRNA splicing endonuclease (SEN) subunits to mitochondria...
October 1, 2018: Genes & Development
Asako McCloskey, Arkaitz Ibarra, Martin W Hetzer
The total number of nuclear pore complexes (NPCs) per nucleus varies greatly between different cell types and is known to change during cell differentiation and cell transformation. However, the underlying mechanisms that control how many nuclear transport channels are assembled into a given nuclear envelope remain unclear. Here, we report that depletion of the NPC basket protein Tpr, but not Nup153, dramatically increases the total NPC number in various cell types. This negative regulation of Tpr occurs via a phosphorylation cascade of extracellular signal-regulated kinase (ERK), the central kinase of the mitogen-activated protein kinase (MAPK) pathway...
October 1, 2018: Genes & Development
Karine Pozo, John D Minna, Jane E Johnson
No abstract text is available yet for this article.
September 1, 2018: Genes & Development
Michael J Smith, Eric E Bryant, Rodney Rothstein
During homologous recombination, cells must coordinate repair, DNA damage checkpoint signaling, and movement of chromosomal loci to facilitate homology search. In Saccharomyces cerevisiae , increased movement of damaged loci (local mobility) and undamaged loci (global mobility) precedes homolog pairing in mitotic cells. How cells modulate chromosome mobility in response to DNA damage remains unclear. Here, we demonstrate that global chromosome mobility is regulated by the Rad51 recombinase and its mediator, Rad52...
September 1, 2018: Genes & Development
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