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Genes & Development

Akie Shimotohno, Renze Heidstra, Ikram Blilou, Ben Scheres
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)...
July 17, 2018: Genes & Development
Meaghan Van Alstyne, Christian M Simon, S Pablo Sardi, Lamya S Shihabuddin, George Z Mentis, Livio Pellizzoni
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...
July 16, 2018: Genes & Development
Victoria L Nelson, Hoang C B Nguyen, Juan C Garcìa-Cañaveras, Erika R Briggs, Wesley Y Ho, Joanna R DiSpirito, Jill M Marinis, David A Hill, Mitchell A Lazar
The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that peritoneal macrophage respiration is enhanced by rosiglitazone, an activating PPARγ ligand, in a PPARγ-dependent manner. Moreover, PPARγ is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPARγ dramatically affects the oxidation of glutamine. Both glutamine and PPARγ have been implicated in alternative activation (AA) of macrophages, and PPARγ was required for interleukin 4 (IL4)-dependent gene expression and stimulation of macrophage respiration...
July 13, 2018: Genes & Development
María García-Rubio, Paula Aguilera, Juan Lafuente-Barquero, José F Ruiz, Marie-Noelle Simon, Vincent Geli, Ana G Rondón, Andrés Aguilera
R loops are an important source of genome instability, largely due to their negative impact on replication progression. Yra1/ALY is an abundant RNA-binding factor conserved from yeast to humans and required for mRNA export, but its excess causes lethality and genome instability. Here, we show that, in addition to ssDNA and ssRNA, Yra1 binds RNA-DNA hybrids in vitro and, when artificially overexpressed, can be recruited to chromatin in an RNA-DNA hybrid-dependent manner, stabilizing R loops and converting them into replication obstacles in vivo...
June 28, 2018: Genes & Development
Yingying Zhang, Aaron Burberry, Jin-Yuan Wang, Jackson Sandoe, Sulagna Ghosh, Namrata D Udeshi, Tanya Svinkina, Daniel A Mordes, Joanie Mok, Maura Charlton, Quan-Zhen Li, Steven A Carr, Kevin Eggan
While a mutation in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS), much remains to be learned concerning the function of the protein normally encoded at this locus. To elaborate further on functions for C9ORF72, we used quantitative mass spectrometry-based proteomics to identify interacting proteins in motor neurons and found that its long isoform complexes with and stabilizes SMCR8, which further enables interaction with WDR41. To study the organismal and cellular functions for this tripartite complex, we generated Smcr8 loss-of-function mutant mice and found that they developed phenotypes also observed in C9orf72 loss-of-function animals, including autoimmunity...
June 27, 2018: Genes & Development
Ryan W Hunter, Yangjian Liu, Hema Manjunath, Asha Acharya, Benjamin T Jones, He Zhang, Beibei Chen, Harini Ramalingam, Robert E Hammer, Yang Xie, James A Richardson, Dinesh Rakheja, Thomas J Carroll, Joshua T Mendell
Loss of function of the DIS3L2 exoribonuclease is associated with Wilms tumor and the Perlman congenital overgrowth syndrome. LIN28, a Wilms tumor oncoprotein, triggers the DIS3L2-mediated degradation of the precursor of let-7, a microRNA that inhibits Wilms tumor development. These observations have led to speculation that DIS3L2-mediated tumor suppression is attributable to let-7 regulation. Here we examine new DIS3L2-deficient cell lines and mouse models, demonstrating that DIS3L2 loss has no effect on mature let-7 levels...
June 27, 2018: Genes & Development
Navasona Krishnan, Christy Felice, Keith Rivera, Darryl J Pappin, Nicholas K Tonks
The levels of copper, which is an essential element in living organisms, are under tight homeostatic control. Inactivating mutations in ATP7B, a P-type Cu-ATPase that functions in copper excretion, promote aberrant accumulation of the metal, primarily the in liver and brain. This condition underlies Wilson's disease, a severe autosomal recessive disorder characterized by profound hepatic and neurological deficits. Current treatment regimens rely on the use of broad specificity metal chelators as "decoppering" agents; however, there are side effects that limit their effectiveness...
June 26, 2018: Genes & Development
Erica A Golemis, Paul Scheet, Tim N Beck, Ed Scolnick, David J Hunter, Ernest Hawk, Nancy Hopkins
Annually, there are 1.6 million new cases of cancer and nearly 600,000 cancer deaths in the United States alone. The public health burden associated with these numbers has motivated enormous research efforts into understanding the root causes of cancer. These efforts have led to the recognition that between 40% and 45% of cancers are associated with preventable risk factors and, importantly, have identified specific molecular mechanisms by which these exposures modify human physiology to induce or promote cancer...
June 26, 2018: Genes & Development
Takayuki Okano-Uchida, Lindsey N Kent, Madhu M Ouseph, Britney McCarty, Jeffrey J Frank, Raleigh Kladney, Maria C Cuitino, John C Thompson, Vincenzo Coppola, Maki Asano, Gustavo Leone
The largest subunit of the origin recognition complex (ORC1) is essential for assembly of the prereplicative complex, firing of DNA replication origins, and faithful duplication of the genome. Here, we generated knock-in mice with LoxP sites flanking exons encoding the critical ATPase domain of ORC1. Global or tissue-specific ablation of ORC1 function in mouse embryo fibroblasts and fetal and adult diploid tissues blocked DNA replication, cell lineage expansion, and organ development. Remarkably, ORC1 ablation in extraembryonic trophoblasts and hepatocytes, two polyploid cell types in mice, failed to impede genome endoreduplication and organ development and function...
July 1, 2018: Genes & Development
Jahan-Yar Parsa, Selim Boudoukha, Jordan Burke, Christina Homer, Hiten D Madhani
In Schizosaccharomyces pombe , transcripts derived from the pericentromeric dg and dh repeats promote heterochromatin formation via RNAi as well as an RNAi-independent mechanism involving the RNA polymerase II (RNAPII)-associated RNA-binding protein Seb1 and RNA processing activities. We show that Seb1 promotes long-lived RNAPII pauses at pericentromeric repeat regions and that their presence correlates with the heterochromatin-triggering activities of the corresponding dg and dh DNA fragments. Globally increasing RNAPII stalling by other means induces the formation of novel large ectopic heterochromatin domains...
July 1, 2018: Genes & Development
Kyoung Mi Kim, Ji Heon Noh, Monica Bodogai, Jennifer L Martindale, Poonam R Pandey, Xiaoling Yang, Arya Biragyn, Kotb Abdelmohsen, Myriam Gorospe
The senescence-associated secretory phenotype (SASP) is a major trait of senescent cells, but the molecular regulators of SASP factor secretion are poorly understood. Mass spectrometry analysis revealed that secretory carrier membrane protein 4 (SCAMP4) levels were strikingly elevated on the surface of senescent cells compared with proliferating cells. Interestingly, silencing SCAMP4 in senescent fibroblasts reduced the secretion of SASP factors, including interleukin 6 (IL6), IL8, growth differentiation factor 15 (GDF-15), C-X-C motif chemokine ligand 1 (CXCL1), and IL7, while, conversely, SCAMP4 overexpression in proliferating fibroblasts increased SASP factor secretion...
July 1, 2018: Genes & Development
Karine Pozo, John D Minna, Jane E Johnson
Tumor heterogeneity of a primary histologic cancer type has major implications for cancer research and therapeutics. An important and understudied aspect of this heterogeneity is the role of transcription factors that serve as "lineage oncogenes" in a tumor type. A demonstration that different subgroups have distinct dependencies on lineage-specific transcription factors is highlighted in a relatively homogenous cancer type: the pulmonary neuroendocrine cancer small cell lung carcinoma (SCLC). Identification of these factors is providing new insights into the origin of the heterogeneity and subtype-specific vulnerabilities in SCLC and provides a template for studying heterogeneity in other cancer types...
July 1, 2018: Genes & Development
Yu-Han Huang, Olaf Klingbeil, Xue-Yan He, Xiaoli S Wu, Gayatri Arun, Bin Lu, Tim D D Somerville, Joseph P Milazzo, John E Wilkinson, Osama E Demerdash, David L Spector, Mikala Egeblad, Junwei Shi, Christopher R Vakoc
Small cell lung cancer (SCLC) is widely considered to be a tumor of pulmonary neuroendocrine cells; however, a variant form of this disease has been described that lacks neuroendocrine features. Here, we applied domain-focused CRISPR screening to human cancer cell lines to identify the transcription factor (TF) POU2F3 (POU class 2 homeobox 3; also known as SKN-1a/OCT-11) as a powerful dependency in a subset of SCLC lines. An analysis of human SCLC specimens revealed that POU2F3 is expressed exclusively in variant SCLC tumors that lack expression of neuroendocrine markers and instead express markers of a chemosensory lineage known as tuft cells...
July 1, 2018: Genes & Development
Khadar Abdi, Chay T Kuo
During mammalian brain development, radial glial progenitors balance between proliferation and differentiation to generate the laminated cortical layers in a temporally precise fashion. Defects in the individual steps going into this complex organogenesis can result in cortical malformations and human nervous system disorders. In this issue of Genes & Development , Liu and colleagues (pp. 763-780) present experimental evidence that an evolutionarily conserved cellular polarity gene, Pard3 ( partitioning-defective 3 ), controls the balance of radial glial proliferation and differentiation through interaction with the Hippo signal transduction pathway...
June 1, 2018: Genes & Development
Shenghong Ma, Kun-Liang Guan
Mutations in PKD1 and PKD2 are the leading cause of autosomal dominant polycystic kidney disease (ADPKD). In this issue of Genes & Development, a report by Cai and colleagues (pp. 781-793) reveals new insight into the molecular basis by which PKD1 deficiency leads to cystic kidney pathogenesis. By using extensive mouse genetic analyses coupled with in vitro cystic assays, the investigators delineate a RhoA-YAP-c-Myc signaling axis as a key downstream from PKD1 deficiency in ADPKD pathogenesis. Their findings provide evidence that the Hippo pathway could be a potential target for treating ADPKD...
June 1, 2018: Genes & Development
Zhongliang Zhao, Nevcin Sentürk, Chenlin Song, Ingrid Grummt
Attenuation of pre-rRNA synthesis in response to elevated temperature is accompanied by increased levels of PAPAS ("promoter and pre-rRNA antisense") , a long noncoding RNA (lncRNA) that is transcribed in an orientation antisense to pre-rRNA. Here we show that PAPAS interacts directly with DNA, forming a DNA-RNA triplex structure that tethers PAPAS to a stretch of purines within the enhancer region, thereby guiding associated CHD4/NuRD (nucleosome remodeling and deacetylation) to the rDNA promoter...
June 1, 2018: Genes & Development
Sang-Kyu Kim, Deborah A Knight, Lisa R Jones, Stephin Vervoort, Ashley P Ng, John F Seymour, James E Bradner, Michaela Waibel, Lev Kats, Ricky W Johnstone
Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL...
June 1, 2018: Genes & Development
Michael Charles Lanz, Susannah Oberly, Ethan James Sanford, Sushma Sharma, Andrei Chabes, Marcus Bustamante Smolka
The Mec1/ATR kinase coordinates multiple cellular responses to replication stress. In addition to its canonical role in activating the checkpoint kinase Rad53, Mec1 also plays checkpoint-independent roles in genome maintenance that are not well understood. Here we used a combined genetic-phosphoproteomic approach to manipulate Mec1 activation and globally monitor Mec1 signaling, allowing us to delineate distinct checkpoint-independent modes of Mec1 action. Using cells in which endogenous Mec1 activators were genetically ablated, we found that expression of "free" Mec1 activation domains (MADs) can robustly activate Mec1 and rescue the severe DNA replication and growth defects of these cells back to wild-type levels...
June 1, 2018: Genes & Development
Wenying Angela Liu, She Chen, Zhizhong Li, Choong Heon Lee, Ghayda Mirzaa, William B Dobyns, M Elizabeth Ross, Jiangyang Zhang, Song-Hai Shi
Proper organization and orderly mitosis of radial glial progenitors (RGPs) drive the formation of a laminated mammalian cortex in the correct size. However, the molecular underpinnings of the intricate process remain largely unclear. Here we show that RGP behavior and cortical development are controlled by temporally distinct actions of partitioning-defective 3 (PARD3) in concert with dynamic HIPPO signaling. RGPs lacking PARD3 exhibit developmental stage-dependent abnormal switches in division mode, resulting in an initial overproduction of RGPs located largely outside the ventricular zone at the expense of deep-layer neurons...
June 1, 2018: Genes & Development
Riki Terui, Koji Nagao, Yoshitaka Kawasoe, Kanae Taki, Torahiko L Higashi, Seiji Tanaka, Takuro Nakagawa, Chikashi Obuse, Hisao Masukata, Tatsuro S Takahashi
Post-replicative correction of replication errors by the mismatch repair (MMR) system is critical for suppression of mutations. Although the MMR system may need to handle nucleosomes at the site of chromatin replication, how MMR occurs in the chromatin environment remains unclear. Here, we show that nucleosomes are excluded from a >1-kb region surrounding a mismatched base pair in Xenopus egg extracts. The exclusion was dependent on the Msh2-Msh6 mismatch recognition complex but not the Mlh1-containing MutL homologs and counteracts both the HIRA- and CAF-1 (chromatin assembly factor 1)-mediated chromatin assembly pathways...
June 1, 2018: Genes & Development
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