Reviewers, Volume 32 (2018) [Reviewers]
(Source: Genes and Development)
Source: Genes and Development - December 3, 2018 Category: Genetics & Stem Cells Tags: Reviewers Source Type: research

Corrigendum: SPATA2 regulates the activation of RIPK1 by modulating linear ubiquitination [Corrigendum]
(Source: Genes and Development)
Source: Genes and Development - December 3, 2018 Category: Genetics & Stem Cells Authors: Wei, R., Xu, L. W., Liu, J., Li, Y., Zhang, P., Shan, B., Lu, X., Qian, L., Wu, Z., Dong, K., Zhu, H., Pan, L., Yuan, J., Pan, H. Tags: Corrigendum Source Type: research

Phosphorylation by the stress-activated MAPK Slt2 down-regulates the yeast TOR complex 2 [Research Papers]
Saccharomyces cerevisiae target of rapamycin (TOR) complex 2 (TORC2) is an essential regulator of plasma membrane lipid and protein homeostasis. How TORC2 activity is modulated in response to changes in the status of the cell envelope is unclear. Here we document that TORC2 subunit Avo2 is a direct target of Slt2, the mitogen-activated protein kinase (MAPK) of the cell wall integrity pathway. Activation of Slt2 by overexpression of a constitutively active allele of an upstream Slt2 activator (Pkc1) or by auxin-induced degradation of a negative Slt2 regulator (Sln1) caused hyperphosphorylation of Avo2 at its MAPK phosphoacc...
Source: Genes and Development - December 3, 2018 Category: Genetics & Stem Cells Authors: Leskoske, K. L., Roelants, F. M., Emmerstorfer-Augustin, A., Augustin, C. M., Si, E. P., Hill, J. M., Thorner, J. Tags: Research Papers Source Type: research

Prefoldin 6 mediates longevity response from heat shock factor 1 to FOXO in C. elegans [Research Papers]
Heat shock factor 1 (HSF-1) and forkhead box O (FOXO) are key transcription factors that protect cells from various stresses. In Caenorhabditis elegans, HSF-1 and FOXO together promote a long life span when insulin/IGF-1 signaling (IIS) is reduced. However, it remains poorly understood how HSF-1 and FOXO cooperate to confer IIS-mediated longevity. Here, we show that prefoldin 6 (PFD-6), a component of the molecular chaperone prefoldin-like complex, relays longevity response from HSF-1 to FOXO under reduced IIS. We found that PFD-6 was specifically required for reduced IIS-mediated longevity by acting in the intestine and h...
Source: Genes and Development - December 3, 2018 Category: Genetics & Stem Cells Authors: Son, H. G., Seo, K., Seo, M., Park, S., Ham, S., An, S. W. A., Choi, E.-S., Lee, Y., Baek, H., Kim, E., Ryu, Y., Ha, C. M., Hsu, A.-L., Roh, T.-Y., Jang, S. K., Lee, S.-J. V. Tags: Research Papers Source Type: research

Multilayered gene control drives timely exit from the stem cell state in uncommitted progenitors during Drosophila asymmetric neural stem cell division [Research Papers]
Self-renewal genes maintain stem cells in an undifferentiated state by preventing the commitment to differentiate. Robust inactivation of self-renewal gene activity following asymmetric stem cell division allows uncommitted stem cell progeny to exit from an undifferentiated state and initiate the commitment to differentiate. Nonetheless, how self-renewal gene activity at mRNA and protein levels becomes synchronously terminated in uncommitted stem cell progeny is unclear. We demonstrate that a multilayered gene regulation system terminates self-renewal gene activity at all levels in uncommitted stem cell progeny in the fly ...
Source: Genes and Development - December 3, 2018 Category: Genetics & Stem Cells Authors: Komori, H., Golden, K. L., Kobayashi, T., Kageyama, R., Lee, C.-Y. Tags: Research Papers Source Type: research

BAP1 regulation of the key adaptor protein NCoR1 is critical for {gamma}-globin gene repression [Research Papers]
Human globin gene production transcriptionally "switches" from fetal to adult synthesis shortly after birth and is controlled by macromolecular complexes that enhance or suppress transcription by cis elements scattered throughout the locus. The DRED (direct repeat erythroid-definitive) repressor is recruited to the -globin and -globin promoters by the orphan nuclear receptors TR2 (NR2C1) and TR4 (NR2C2) to engender their silencing in adult erythroid cells. Here we found that nuclear receptor corepressor-1 (NCoR1) is a critical component of DRED that acts as a scaffold to unite the DNA-binding and epigenetic enzym...
Source: Genes and Development - December 3, 2018 Category: Genetics & Stem Cells Authors: Yu, L., Jearawiriyapaisarn, N., Lee, M. P., Hosoya, T., Wu, Q., Myers, G., Lim, K.-C., Kurita, R., Nakamura, Y., Vojtek, A. B., Rual, J.-F., Engel, J. D. Tags: Research Papers Source Type: research

Maternal Eed knockout causes loss of H3K27me3 imprinting and random X inactivation in the extraembryonic cells [Research Papers]
Genomic imprinting is essential for mammalian development. Recent studies have revealed that maternal histone H3 Lys27 trimethylation (H3K27me3) can mediate DNA methylation-independent genomic imprinting. However, the regulatory mechanisms and functions of this new imprinting mechanism are largely unknown. Here we demonstrate that maternal Eed, an essential component of the Polycomb group complex 2 (PRC2), is required for establishing H3K27me3 imprinting. We found that all H3K27me3-imprinted genes, including Xist, lose their imprinted expression in Eed maternal knockout (matKO) embryos, resulting in male-biased lethality. ...
Source: Genes and Development - December 3, 2018 Category: Genetics & Stem Cells Authors: Inoue, A., Chen, Z., Yin, Q., Zhang, Y. Tags: Research Papers Source Type: research

Toxicity of overexpressed MeCP2 is independent of HDAC3 activity [Research Papers]
Duplication of the X-linked MECP2 gene causes a severe neurological syndrome whose molecular basis is poorly understood. To determine the contribution of known functional domains to overexpression toxicity, we engineered a mouse model that expresses wild-type or mutated MeCP2 from the Mapt (Tau) locus in addition to the endogenous protein. Animals that expressed approximately four times the wild-type level of MeCP2 failed to survive to weaning. Strikingly, a single amino acid substitution that prevents MeCP2 from binding to the TBL1X(R1) subunit of nuclear receptor corepressor 1/2 (NCoR1/2) complexes, when expressed at equ...
Source: Genes and Development - December 3, 2018 Category: Genetics & Stem Cells Authors: Koerner, M. V., FitzPatrick, L., Selfridge, J., Guy, J., De Sousa, D., Tillotson, R., Kerr, A., Sun, Z., Lazar, M. A., Lyst, M. J., Bird, A. Tags: Research Papers Source Type: research

Adaptation to DNA damage checkpoint in senescent telomerase-negative cells promotes genome instability [Research Papers]
In cells lacking telomerase, telomeres gradually shorten during each cell division to reach a critically short length, permanently activate the DNA damage checkpoint, and trigger replicative senescence. The increase in genome instability that occurs as a consequence may contribute to the early steps of tumorigenesis. However, because of the low frequency of mutations and the heterogeneity of telomere-induced senescence, the timing and mechanisms of genome instability increase remain elusive. Here, to capture early mutation events during replicative senescence, we used a combined microfluidic-based approach and live-cell im...
Source: Genes and Development - December 3, 2018 Category: Genetics & Stem Cells Authors: Coutelier, H., Xu, Z., Morisse, M. C., Lhuillier-Akakpo, M., Pelet, S., Charvin, G., Dubrana, K., Teixeira, M. T. Tags: Research Papers Source Type: research

Genetic interactions between specific chromosome copy number alterations dictate complex aneuploidy patterns [Research Papers]
Cells that contain an abnormal number of chromosomes are called aneuploid. High rates of aneuploidy in cancer are correlated with an increased frequency of chromosome missegregation, termed chromosomal instability (CIN). Both high levels of aneuploidy and CIN are associated with cancers that are resistant to treatment. Although aneuploidy and CIN are typically detrimental to cell growth, they can aid in adaptation to selective pressures. Here, we induced extremely high rates of chromosome missegregation in yeast to determine how cells adapt to CIN over time. We found that adaptation to CIN occurs initially through many dif...
Source: Genes and Development - December 3, 2018 Category: Genetics & Stem Cells Authors: Ravichandran, M. C., Fink, S., Clarke, M. N., Hofer, F. C., Campbell, C. S. Tags: Research Papers Source Type: research

RNA m6 A modification enzymes shape innate responses to DNA by regulating interferon {beta} [Research Papers]
Modification of mRNA by N6-adenosine methylation (m6A) on internal bases influences gene expression in eukaryotes. How the dynamic genome-wide landscape of m6A-modified mRNAs impacts virus infection and host immune responses remains poorly understood. Here, we show that type I interferon (IFN) production triggered by dsDNA or human cytomegalovirus (HCMV) is controlled by the cellular m6A methyltrasferase subunit METTL14 and ALKBH5 demethylase. While METTL14 depletion reduced virus reproduction and stimulated dsDNA- or HCMV-induced IFNB1 mRNA accumulation, ALKBH5 depletion had the opposite effect. Depleting METTL14 increase...
Source: Genes and Development - December 3, 2018 Category: Genetics & Stem Cells Authors: Rubio, R. M., Depledge, D. P., Bianco, C., Thompson, L., Mohr, I. Tags: Research Papers Source Type: research

Repairing the lungs one breath at a time: How dedicated or facultative are you? [Reviews]
Tissue regeneration involves various types of cellular and molecular responses depending on the type of tissue and the injury or disease that is inflicted. While many tissues contain dedicated stem/progenitor cell lineages, many others contain cells that, during homeostasis, are considered physiologically functional and fully differentiated but, after injury or in disease states, exhibit stem/progenitor-like activity. Recent identification of subsets of defined cell types as facultative stem/progenitor cells has led to a re-examination of how certain tissues respond to injury to mount a regenerative response. In this revie...
Source: Genes and Development - December 3, 2018 Category: Genetics & Stem Cells Authors: Leach, J. P., Morrisey, E. E. Tags: Development, Stem & Progenitor Cells Reviews Source Type: research

Evolution of aneuploidy: overcoming the original CIN [Outlook]
Chromosomal instability (CIN) generates continuously novel aneuploid genomes—unbalanced chromosome combinations that differ from the haploid chromosome set and its multiples. On one hand, this causes problems for cells, as high CIN and aneuploidy impair cellular proliferation by inducing multiple cellular stresses. At the same time, some genomes might provide an advantage under suboptimal conditions. However, what happens to cells that carry a mutation generating extremely high CIN? Are they sentenced to death, or can their instability help them to avert that fate? The elegant work from Ravichandran and colleagues (p...
Source: Genes and Development - December 3, 2018 Category: Genetics & Stem Cells Authors: Storchova, Z. Tags: Chromosome Dynamics and Nuclear Architecture Outlook Source Type: research

Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/{beta}-catenin signaling [Research Papers]
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...
Source: Genes and Development - November 1, 2018 Category: Genetics & Stem Cells Authors: Cantu, C., Felker, A., Zimmerli, D., Prummel, K. D., Cabello, E. M., Chiavacci, E., Mendez-Acevedo, K. M., Kirchgeorg, L., Burger, S., Ripoll, J., Valenta, T., Hausmann, G., Vilain, N., Aguet, M., Burger, A., Panakova, D., Basler, K., Mosimann, C. Tags: Research Papers Source Type: research

Enhancer, transcriptional, and cell fate plasticity precedes intestinal determination during endoderm development [Research Papers]
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. Depletion of the intestinal TF CDX...
Source: Genes and Development - November 1, 2018 Category: Genetics & Stem Cells Authors: Banerjee, K. K., Saxena, M., Kumar, N., Chen, L., Cavazza, A., Toke, N. H., O'Neill, N. K., Madha, S., Jadhav, U., Verzi, M. P., Shivdasani, R. A. Tags: Research Papers Source Type: research

Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development [Research Papers]
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. Accordingly, TRP53 mutant proteins impa...
Source: Genes and Development - November 1, 2018 Category: Genetics & Stem Cells Authors: Aubrey, B. J., Janic, A., Chen, Y., Chang, C., Lieschke, E. C., Diepstraten, S. T., Kueh, A. J., Bernardini, J. P., Dewson, G., O'Reilly, L. A., Whitehead, L., Voss, A. K., Smyth, G. K., Strasser, A., Kelly, G. L. Tags: Research Papers Source Type: research

Post-translational modification localizes MYC to the nuclear pore basket to regulate a subset of target genes involved in cellular responses to environmental signals [Research Papers]
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 assoc...
Source: Genes and Development - November 1, 2018 Category: Genetics & Stem Cells Authors: Su, Y., Pelz, C., Huang, T., Torkenczy, K., Wang, X., Cherry, A., Daniel, C. J., Liang, J., Nan, X., Dai, M.-S., Adey, A., Impey, S., Sears, R. C. Tags: Research Papers Source Type: research

A C9orf72-CARM1 axis regulates lipid metabolism under glucose starvation-induced nutrient stress [Research Papers]
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. C9orf72 acts by promoting the lysosomal degradation of coactivator-associated arginine methyltransferase 1 (CARM1), which in turn regulates autophagy–lysosomal functions and lipid metabolism. In ALS/FTD pat...
Source: Genes and Development - November 1, 2018 Category: Genetics & Stem Cells Authors: Liu, Y., Wang, T., Ji, Y. J., Johnson, K., Liu, H., Johnson, K., Bailey, S., Suk, Y., Lu, Y.-N., Liu, M., Wang, J. Tags: Research Papers Source Type: research

Requirement for NF-{kappa}B in maintenance of molecular and behavioral circadian rhythms in mice [Research Papers]
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-B in response to inflammatory stimuli leads to marked inhibition of clock repressors, including the Period, Cryptochrome, and Rev-erb genes, within the negative limb. Furthermore, activa...
Source: Genes and Development - November 1, 2018 Category: Genetics & Stem Cells Authors: Hong, H.-K., Maury, E., Ramsey, K. M., Perelis, M., Marcheva, B., Omura, C., Kobayashi, Y., Guttridge, D. C., Barish, G. D., Bass, J. Tags: Research Papers Source Type: research

LMI1 homeodomain protein regulates organ proportions by spatial modulation of endoreduplication [Research Communications]
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. LM1 acts through directly activating t...
Source: Genes and Development - November 1, 2018 Category: Genetics & Stem Cells Authors: Vuolo, F., Kierzkowski, D., Runions, A., Hajheidari, M., Mentink, R. A., Gupta, M. D., Zhang, Z., Vlad, D., Wang, Y., Pecinka, A., Gan, X., Hay, A., Huijser, P., Tsiantis, M. Tags: Research Communications Source Type: research

Cross-regulatory circuits linking inflammation, high-fat diet, and the circadian clock [Outlook]
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. 1367–1379) studied how acute and chronic inflammation interacts with the circadia...
Source: Genes and Development - November 1, 2018 Category: Genetics & Stem Cells Authors: Gachon, F., Yeung, J., Naef, F. Tags: Molecular Physiology and Metabolism, Chromatin and Gene Expression Outlook Source Type: research

Corrigendum: p53 is essential for DNA methylation homeostasis in naïve embryonic stem cells, and its loss promotes clonal heterogeneity [Corrigendum]
(Source: Genes and Development)
Source: Genes and Development - October 1, 2018 Category: Genetics & Stem Cells Authors: Tovy, A., Spiro, A., McCarthy, R., Shipony, Z., Aylon, Y., Allton, K., Ainbinder, E., Furth, N., Tanay, A., Barton, M., Oren, M. Tags: Corrigendum Source Type: research

Single-nucleus transcriptomic survey of cell diversity and functional maturation in postnatal mammalian hearts [Resource/Methodology]
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 bia...
Source: Genes and Development - October 1, 2018 Category: Genetics & Stem Cells Authors: Hu, P., Liu, J., Zhao, J., Wilkins, B. J., Lupino, K., Wu, H., Pei, L. Tags: Resource/Methodology Source Type: research

Arabidopsis RUP2 represses UVR8-mediated flowering in noninductive photoperiods [Research Papers]
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 photorecept...
Source: Genes and Development - October 1, 2018 Category: Genetics & Stem Cells Authors: Arongaus, A. B., Chen, S., Pireyre, M., Glöckner, N., Galvao, V. C., Albert, A., Winkler, J. B., Fankhauser, C., Harter, K., Ulm, R. Tags: Research Papers Source Type: research

Tpr regulates the total number of nuclear pore complexes per cell nucleus [Research Papers]
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-activate...
Source: Genes and Development - October 1, 2018 Category: Genetics & Stem Cells Authors: McCloskey, A., Ibarra, A., Hetzer, M. W. Tags: Research Papers Source Type: research

DNA polymerase {varepsilon}-dependent modulation of the pausing property of the CMG helicase at the barrier [Research Communications]
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 leadin...
Source: Genes and Development - October 1, 2018 Category: Genetics & Stem Cells Authors: Hizume, K., Endo, S., Muramatsu, S., Kobayashi, T., Araki, H. Tags: Research Communications Source Type: research

From powerhouse to processing plant: conserved roles of mitochondrial outer membrane proteins in tRNA splicing [Research Communications]
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. Schizosaccharomyces pombe SEN subunits also localize to mitochondria, and Tom70 is required for this localization and pre-tRNA splicing. Thus, the role of MOM prote...
Source: Genes and Development - October 1, 2018 Category: Genetics & Stem Cells Authors: Wan, Y., Hopper, A. K. Tags: Research Communications Source Type: research

The aryl hydrocarbon receptor regulates nucleolar activity and protein synthesis in MYC-expressing cells [Research Communications]
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. Therefore, targeting AHR or its downstre...
Source: Genes and Development - October 1, 2018 Category: Genetics & Stem Cells Authors: Lafita-Navarro, M. C., Kim, M., Borenstein-Auerbach, N., Venkateswaran, N., Hao, Y.-H., Ray, R., Brabletz, T., Scaglioni, P. P., Shay, J. W., Conacci-Sorrell, M. Tags: Research Communications Source Type: research

Regulatory cocktail for dopaminergic neurons in a protovertebrate identified by whole-embryo single-cell transcriptomics [Research Communications]
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 o...
Source: Genes and Development - October 1, 2018 Category: Genetics & Stem Cells Authors: Horie, T., Horie, R., Chen, K., Cao, C., Nakagawa, M., Kusakabe, T. G., Satoh, N., Sasakura, Y., Levine, M. Tags: Research Communications Source Type: research

Pathways to balance mitochondrial translation and protein import [Reviews]
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 physiologica...
Source: Genes and Development - October 1, 2018 Category: Genetics & Stem Cells Authors: Priesnitz, C., Becker, T. Tags: Molecular Physiology and Metabolism, Translation Reviews Source Type: research

Roles of the immune system in cancer: from tumor initiation to metastatic progression [Reviews]
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 c...
Source: Genes and Development - October 1, 2018 Category: Genetics & Stem Cells Authors: Gonzalez, H., Hagerling, C., Werb, Z. Tags: Cancer and Disease Models, Immunology Reviews Source Type: research

Corrigendum: Identifying a missing lineage driver in a subset of lung neuroendocrine tumors [Corrigendum]
(Source: Genes and Development)
Source: Genes and Development - September 4, 2018 Category: Genetics & Stem Cells Authors: Pozo, K., Minna, J. D., Johnson, J. E. Tags: Corrigendum Source Type: research

Distinct patterns of histone acetyltransferase and Mediator deployment at yeast protein-coding genes [Research Papers]
The transcriptional coactivators Mediator and two histone acetyltransferase (HAT) complexes, NuA4 and SAGA, play global roles in transcriptional activation. Here we explore the relative contributions of these factors to RNA polymerase II association at specific genes and gene classes by rapid nuclear depletion of key complex subunits. We show that the NuA4 HAT Esa1 differentially affects certain groups of genes, whereas the SAGA HAT Gcn5 has a weaker but more uniform effect. Relative dependence on Esa1 and Tra1, a shared component of NuA4 and SAGA, distinguishes two large groups of coregulated growth-promoting genes. In co...
Source: Genes and Development - September 4, 2018 Category: Genetics & Stem Cells Authors: Bruzzone, M. J., Grünberg, S., Kubik, S., Zentner, G. E., Shore, D. Tags: Research Papers Source Type: research

Increased chromosomal mobility after DNA damage is controlled by interactions between the recombination machinery and the checkpoint [Research Papers]
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. Surprisingly, rad51 rad52 cells display checkpoint-dependent constitutively increased mobility, indicating that...
Source: Genes and Development - September 4, 2018 Category: Genetics & Stem Cells Authors: Smith, M. J., Bryant, E. E., Rothstein, R. Tags: Research Papers Source Type: research

Functions of unconventional mammalian translational GTPases GTPBP1 and GTPBP2 [Research Papers]
GTP-binding protein 1 (GTPBP1) and GTPBP2 comprise a divergent group of translational GTPases with obscure functions, which are most closely related to eEF1A, eRF3, and Hbs1. Although recent reports implicated GTPBPs in mRNA surveillance and ribosome-associated quality control, how they perform these functions remains unknown. Here, we demonstrate that GTPBP1 possesses eEF1A-like elongation activity, delivering cognate aminoacyl-transfer RNA (aa-tRNA) to the ribosomal A site in a GTP-dependent manner. It also stimulates exosomal degradation of mRNAs in elongation complexes. The kinetics of GTPBP1-mediated elongation argues...
Source: Genes and Development - September 4, 2018 Category: Genetics & Stem Cells Authors: Zinoviev, A., Goyal, A., Jindal, S., LaCava, J., Komar, A. A., Rodnina, M. V., Hellen, C. U. T., Pestova, T. V. Tags: Research Papers Source Type: research

Dynamic turnover of paused Pol II complexes at human promoters [Research Papers]
We report that most 5' paused Pol II throughout the genome is turned over within 2 min. This process is revealed under hypertonic conditions that prevent Pol II recruitment to promoters. This turnover requires cell viability but is not prevented by inhibiting transcription elongation, suggesting that it is mediated at the level of termination. When initiation was prevented by triptolide during recovery from high salt, a novel preinitiated state of Pol II lacking the pausing factor Spt5 accumulated at transcription start sites. We propose that Pol II occupancy near 5' ends is governed by a cycle of ongoing assembly of prein...
Source: Genes and Development - September 4, 2018 Category: Genetics & Stem Cells Authors: Erickson, B., Sheridan, R. M., Cortazar, M., Bentley, D. L. Tags: Research Papers Source Type: research

Merlin/ERM proteins regulate growth factor-induced macropinocytosis and receptor recycling by organizing the plasma membrane:cytoskeleton interface [Research Papers]
The architectural and biochemical features of the plasma membrane are governed by its intimate association with the underlying cortical cytoskeleton. The neurofibromatosis type 2 (NF2) tumor suppressor merlin and closely related membrane:cytoskeleton-linking protein ezrin organize the membrane:cytoskeleton interface, a critical cellular compartment that both regulates and is regulated by growth factor receptors. An example of this poorly understood interrelationship is macropinocytosis, an ancient process of nutrient uptake and membrane remodeling that can both be triggered by growth factors and manage receptor availabilit...
Source: Genes and Development - September 4, 2018 Category: Genetics & Stem Cells Authors: Chiasson-MacKenzie, C., Morris, Z. S., Liu, C.-H., Bradford, W. B., Koorman, T., McClatchey, A. I. Tags: Research Papers Source Type: research

Genetic modifiers of the BRD4-NUT dependency of NUT midline carcinoma uncovers a synergism between BETis and CDK4/6is [Research Papers]
Bromodomain and extraterminal (BET) domain inhibitors (BETis) show efficacy on NUT midline carcinoma (NMC). However, not all NMC patients respond, and responders eventually develop resistance and relapse. Using CRISPR and ORF expression screens, we systematically examined the ability of cancer drivers to mediate resistance of NMC to BETis and uncovered six general classes/pathways mediating resistance. Among these, we showed that RRAS2 attenuated the effect of JQ1 in part by sustaining ERK pathway function during BRD4 inhibition. Furthermore, overexpression of Kruppel-like factor 4 (KLF4), mediated BETi resistance in NMC c...
Source: Genes and Development - September 4, 2018 Category: Genetics & Stem Cells Authors: Liao, S., Maertens, O., Cichowski, K., Elledge, S. J. Tags: Research Papers Source Type: research

STAT3 is a master regulator of epithelial identity and KRAS-driven tumorigenesis [Research Papers]
A dichotomy exists regarding the role of signal transducer and activator of transcription 3 (STAT3) in cancer. Functional and genetic studies demonstrate either an intrinsic requirement for STAT3 or a suppressive effect on common types of cancer. These contrasting actions of STAT3 imply context dependency. To examine mechanisms that underlie STAT3 function in cancer, we evaluated the impact of STAT3 activity in KRAS-driven lung and pancreatic cancer. Our study defines a fundamental and previously unrecognized function of STAT3 in the maintenance of epithelial cell identity and differentiation. Loss of STAT3 preferentially ...
Source: Genes and Development - September 4, 2018 Category: Genetics & Stem Cells Authors: D'Amico, S., Shi, J., Martin, B. L., Crawford, H. C., Petrenko, O., Reich, N. C. Tags: Research Papers Source Type: research

TCF3 alternative splicing controlled by hnRNP H/F regulates E-cadherin expression and hESC pluripotency [Research Papers]
In this study, we first identified transcripts that display specific AS patterns in pluripotent human ESCs (hESCs) relative to differentiated cells. One of these encodes T-cell factor 3 (TCF3), a transcription factor that plays important roles in ESC differentiation. AS creates two TCF3 isoforms, E12 and E47, and we identified two related splicing factors, heterogeneous nuclear ribonucleoproteins (hnRNPs) H1 and F (hnRNP H/F), that regulate TCF3 splicing. We found that hnRNP H/F levels are high in hESCs, leading to high E12 expression, but decrease during differentiation, switching splicing to produce elevated E47 levels. ...
Source: Genes and Development - September 4, 2018 Category: Genetics & Stem Cells Authors: Yamazaki, T., Liu, L., Lazarev, D., Al-Zain, A., Fomin, V., Yeung, P. L., Chambers, S. M., Lu, C.-W., Studer, L., Manley, J. L. Tags: Research Papers Source Type: research

A novel DCL2-dependent miRNA pathway in tomato affects susceptibility to RNA viruses [Research Communications]
Tomato Dicer-like2 (slDCL2) is a key component of resistance pathways against potato virus X (PVX) and tobacco mosaic virus (TMV). It is also required for production of endogenous small RNAs, including miR6026 and other noncanonical microRNAs (miRNAs). The slDCL2 mRNAs are targets of these slDCL2-dependent RNAs in a feedback loop that was disrupted by target mimic RNAs of miR6026. In lines expressing these RNAs, there was correspondingly enhanced resistance against PVX and TMV. These findings illustrate a novel miRNA pathway in plants and a crop protection strategy in which miRNA target mimicry elevates expression of defen...
Source: Genes and Development - September 4, 2018 Category: Genetics & Stem Cells Authors: Wang, Z., Hardcastle, T. J., Pastor, A. C., Yip, W. H., Tang, S., Baulcombe, D. C. Tags: Research Communications Source Type: research

Signaling pathways and steroid receptors modulating estrogen receptor {alpha} function in breast cancer [Reviews]
Estrogen receptor α (ER) is the major driver of ~75% of breast cancers, and multiple ER targeting drugs are routinely used clinically to treat patients with ER+ breast cancer. However, many patients relapse on these targeted therapies and ultimately develop metastatic and incurable disease, and understanding the mechanisms leading to drug resistance is consequently of utmost importance. It is now clear that, in addition to estrogens, ER function is modulated by other steroid receptors and multiple signaling pathways (e.g., growth factor and cytokine signaling), and many of these pathways affect drug resistance and pa...
Source: Genes and Development - September 4, 2018 Category: Genetics & Stem Cells Authors: Siersbaek, R., Kumar, S., Carroll, J. S. Tags: Reviews Source Type: research

Genetics and biology of prostate cancer [Reviews]
Despite the high long-term survival in localized prostate cancer, metastatic prostate cancer remains largely incurable even after intensive multimodal therapy. The lethality of advanced disease is driven by the lack of therapeutic regimens capable of generating durable responses in the setting of extreme tumor heterogeneity on the genetic and cell biological levels. Here, we review available prostate cancer model systems, the prostate cancer genome atlas, cellular and functional heterogeneity in the tumor microenvironment, tumor-intrinsic and tumor-extrinsic mechanisms underlying therapeutic resistance, and technological a...
Source: Genes and Development - September 4, 2018 Category: Genetics & Stem Cells Authors: Wang, G., Zhao, D., Spring, D. J., DePinho, R. A. Tags: Cancer and Disease Models Reviews Source Type: research

Alternative pre-mRNA splicing switch controls hESC pluripotency and differentiation [Outlook]
Alternative splicing (AS) of pre-mRNAs is a ubiquitous process in mammals that is tightly regulated in a cell type- and cell state-dependent manner. However, the details of how splicing is regulated to impact specific cell fate decisions remains incompletely understood. A study by Yamazaki and colleagues (pp. 1161–1174) in this issue of Genes & Development provides exciting new insight into the role and regulation of splicing in the maintenance of pluripotency of human embryonic stem cells (hESCs). In brief, they show that AS of several genes is robustly regulated upon differentiation of hESCs. One of these genes...
Source: Genes and Development - September 4, 2018 Category: Genetics & Stem Cells Authors: Agosto, L. M., Lynch, K. W. Tags: Translation, Stem & Progenitor Cells, Post-transcriptional Control Outlook Source Type: research

Corrigendum: Maf links Neuregulin1 signaling to cholesterol synthesis in myelinating Schwann cells [Corrigendum]
(Source: Genes and Development)
Source: Genes and Development - August 1, 2018 Category: Genetics & Stem Cells Authors: Kim, M., Wende, H., Walcher, J., Kühnemund, J., Cheret, C., Kempa, S., McShane, E., Selbach, M., Lewis, G. R., Birchmeier, C. Tags: Corrigendum Source Type: research

Root stem cell niche organizer specification by molecular convergence of PLETHORA and SCARECROW transcription factor modules [Research Papers]
Continuous formation of somatic tissues in plants requires functional stem cell niches where undifferentiated cells are maintained. In Arabidopsis thaliana, PLETHORA (PLT) and SCARECROW (SCR) genes are outputs of apical–basal and radial patterning systems, and both are required for root stem cell specification and maintenance. The WUSCHEL-RELATED HOMEOBOX 5 (WOX5) gene is specifically expressed in and required for functions of a small group of root stem cell organizer cells, also called the quiescent center (QC). PLT and SCR are required for QC function, and their expression overlaps in the QC; however, how they spec...
Source: Genes and Development - August 1, 2018 Category: Genetics & Stem Cells Authors: Shimotohno, A., Heidstra, R., Blilou, I., Scheres, B. Tags: Research Papers Source Type: research

Deregulation of the G1/S-phase transition is the proximal cause of mortality in old yeast mother cells [Research Papers]
Budding yeast cells produce a finite number of daughter cells before they die. Why old yeast cells stop dividing and die is unclear. We found that age-induced accumulation of the G1/S-phase inhibitor Whi5 and defects in G1/S cyclin transcription cause cell cycle delays and genomic instability that result in cell death. We further identified extrachromosomal rDNA (ribosomal DNA) circles (ERCs) to cause the G1/S cyclin expression defect in old cells. Spontaneous segregation of Whi5 and ERCs into daughter cells rejuvenates old mothers, but daughters that inherit these aging factors die rapidly. Our results identify deregulati...
Source: Genes and Development - August 1, 2018 Category: Genetics & Stem Cells Authors: Neurohr, G. E., Terry, R. L., Sandikci, A., Zou, K., Li, H., Amon, A. Tags: Research Papers Source Type: research

Coordinate regulation of alternative pre-mRNA splicing events by the human RNA chaperone proteins hnRNPA1 and DDX5 [Research Papers]
Alternative premessenger RNA (pre-mRNA) splicing is a post-transcriptional mechanism for controlling gene expression. Splicing patterns are determined by both RNA-binding proteins and nuclear pre-mRNA structure. Here, we analyzed pre-mRNA splicing patterns, RNA-binding sites, and RNA structures near these binding sites coordinately controlled by two splicing factors: the heterogeneous nuclear ribonucleoprotein hnRNPA1 and the RNA helicase DDX5. We identified thousands of alternative pre-mRNA splicing events controlled by these factors by RNA sequencing (RNA-seq) following RNAi. Enhanced cross-linking and immunoprecipitatio...
Source: Genes and Development - August 1, 2018 Category: Genetics & Stem Cells Authors: Lee, Y. J., Wang, Q., Rio, D. C. Tags: Research Papers Source Type: research

Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy [Research Papers]
Ubiquitous deficiency in the survival motor neuron (SMN) protein causes death of motor neurons—a hallmark of the neurodegenerative disease spinal muscular atrophy (SMA)—through poorly understood mechanisms. Here, we show that the function of SMN in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) regulates alternative splicing of Mdm2 and Mdm4, two nonredundant repressors of p53. Decreased inclusion of critical Mdm2 and Mdm4 exons is most prominent in SMA motor neurons and correlates with both snRNP reduction and p53 activation in vivo. Importantly, increased skipping of Mdm2 and Mdm4 exon...
Source: Genes and Development - August 1, 2018 Category: Genetics & Stem Cells Authors: Van Alstyne, M., Simon, C. M., Sardi, S. P., Shihabuddin, L. S., Mentis, G. Z., Pellizzoni, L. Tags: Research Papers Source Type: research

PPAR{gamma} is a nexus controlling alternative activation of macrophages via glutamine metabolism [Research Papers]
The nuclear receptor peroxisome proliferator-activated receptor (PPAR) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that peritoneal macrophage respiration is enhanced by rosiglitazone, an activating PPAR ligand, in a PPAR-dependent manner. Moreover, PPAR is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPAR dramatically affects the oxidation of glutamine. Both glutamine and PPAR have been implicated in alternative activation (AA) of macrophages, and PPAR was required for interleukin 4 (IL4)-dependent gene expression ...
Source: Genes and Development - August 1, 2018 Category: Genetics & Stem Cells Authors: Nelson, V. L., Nguyen, H. C. B., Garcia-Canaveras, J. C., Briggs, E. R., Ho, W. Y., DiSpirito, J. R., Marinis, J. M., Hill, D. A., Lazar, M. A. Tags: Research Papers Source Type: research