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Genes & Development

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https://www.readbyqxmd.com/read/28428263/different-requirements-of-functional-telomeres-in-neural-stem-cells-and-terminally-differentiated-neurons
#1
Anastasia Lobanova, Robert She, Simon Pieraut, Charlie Clapp, Anton Maximov, Eros Lazzerini Denchi
Telomeres have been studied extensively in peripheral tissues, but their relevance in the nervous system remains poorly understood. Here, we examine the roles of telomeres at distinct stages of murine brain development by using lineage-specific genetic ablation of TRF2, an essential component of the shelterin complex that protects chromosome ends from the DNA damage response machinery. We found that functional telomeres are required for embryonic and adult neurogenesis, but their uncapping has surprisingly no detectable consequences on terminally differentiated neurons...
April 20, 2017: Genes & Development
https://www.readbyqxmd.com/read/28428262/uncoupling-neurogenic-gene-networks-in-the-drosophila-embryo
#2
William A Rogers, Yogesh Goyal, Kei Yamaya, Stanislav Y Shvartsman, Michael S Levine
The EGF signaling pathway specifies neuronal identities in the Drosophila embryo by regulating developmental patterning genes such as intermediate neurons defective (ind). EGFR is activated in the ventral midline and neurogenic ectoderm by the Spitz ligand, which is processed by the Rhomboid protease. CRISPR/Cas9 was used to delete defined rhomboid enhancers mediating expression at each site of Spitz processing. Surprisingly, the neurogenic ectoderm, not the ventral midline, was found to be the dominant source of EGF patterning activity...
April 20, 2017: Genes & Development
https://www.readbyqxmd.com/read/28428261/ebf2-transcriptionally-regulates-brown-adipogenesis-via-the-histone-reader-dpf3-and-the-baf-chromatin-remodeling-complex
#3
Suzanne N Shapira, Hee-Woong Lim, Sona Rajakumari, Alexander P Sakers, Jeff Ishibashi, Matthew J Harms, Kyoung-Jae Won, Patrick Seale
The transcription factor early B-cell factor 2 (EBF2) is an essential mediator of brown adipocyte commitment and terminal differentiation. However, the mechanisms by which EBF2 regulates chromatin to activate brown fat-specific genes in adipocytes were unknown. ChIP-seq (chromatin immunoprecipitation [ChIP] followed by deep sequencing) analyses in brown adipose tissue showed that EBF2 binds and regulates the activity of lineage-specific enhancers. Mechanistically, EBF2 physically interacts with the chromatin remodeler BRG1 and the BAF chromatin remodeling complex in brown adipocytes...
April 20, 2017: Genes & Development
https://www.readbyqxmd.com/read/28373207/optogenetic-perturbation-and-bioluminescence-imaging-to-analyze-cell-to-cell-transfer-of-oscillatory-information
#4
Akihiro Isomura, Fumiko Ogushi, Hiroshi Kori, Ryoichiro Kageyama
Cells communicate with each other to coordinate their gene activities at the population level through signaling pathways. It has been shown that many gene activities are oscillatory and that the frequency and phase of oscillatory gene expression encode various types of information. However, whether or how such oscillatory information is transmitted from cell to cell remains unknown. Here, we developed an integrated approach that combines optogenetic perturbations and single-cell bioluminescence imaging to visualize and reconstitute synchronized oscillatory gene expression in signal-sending and signal-receiving processes...
April 3, 2017: Genes & Development
https://www.readbyqxmd.com/read/28373206/structures-of-partition-protein-para-with-nonspecific-dna-and-parb-effector-reveal-molecular-insights-into-principles-governing-walker-box-dna-segregation
#5
Hengshan Zhang, Maria A Schumacher
Walker-box partition systems are ubiquitous in nature and mediate the segregation of bacterial and archaeal DNA. Well-studied plasmid Walker-box partition modules require ParA, centromere-DNA, and a centromere-binding protein, ParB. In these systems, ParA-ATP binds nucleoid DNA and uses it as a substratum to deliver ParB-attached cargo DNA, and ParB drives ParA dynamics, allowing ParA progression along the nucleoid. How ParA-ATP binds nonspecific DNA and is regulated by ParB is unclear. Also under debate is whether ParA polymerizes on DNA to mediate segregation...
April 3, 2017: Genes & Development
https://www.readbyqxmd.com/read/28360182/simultaneous-mapping-of-active-dna-demethylation-and-sister-chromatid-exchange-in-single-cells
#6
Xiaoji Wu, Azusa Inoue, Tsukasa Suzuki, Yi Zhang
To understand mammalian active DNA demethylation, various methods have been developed to map the genomic distribution of the demethylation intermediates 5-formylcysotine (5fC) and 5-carboxylcytosine (5caC). However, the majority of these methods requires a large number of cells to begin with. In this study, we describe low-input methylase-assisted bisulfite sequencing (liMAB-seq ) and single-cell MAB-seq (scMAB-seq), capable of profiling 5fC and 5caC at genome scale using ∼100 cells and single cells, respectively...
March 30, 2017: Genes & Development
https://www.readbyqxmd.com/read/28356341/essential-role-for-centromeric-factors-following-p53-loss-and-oncogenic-transformation
#7
Dan Filipescu, Monica Naughtin, Katrina Podsypanina, Vincent Lejour, Laurence Wilson, Zachary A Gurard-Levin, Guillermo A Orsi, Iva Simeonova, Eleonore Toufektchan, Laura D Attardi, Franck Toledo, Geneviève Almouzni
In mammals, centromere definition involves the histone variant CENP-A (centromere protein A), deposited by its chaperone, HJURP (Holliday junction recognition protein). Alterations in this process impair chromosome segregation and genome stability, which are also compromised by p53 inactivation in cancer. Here we found that CENP-A and HJURP are transcriptionally up-regulated in p53-null human tumors. Using an established mouse embryonic fibroblast (MEF) model combining p53 inactivation with E1A or HRas-V12 oncogene expression, we reproduced a similar up-regulation of HJURP and CENP-A...
March 29, 2017: Genes & Development
https://www.readbyqxmd.com/read/28336516/a-novel-role-of-the-dna2-translocase-function-in-dna-break-resection
#8
Adam S Miller, James M Daley, Nhung Tuyet Pham, Hengyao Niu, Xiaoyu Xue, Grzegorz Ira, Patrick Sung
DNA double-strand break repair by homologous recombination entails nucleolytic resection of the 5' strand at break ends. Dna2, a flap endonuclease with 5'-3' helicase activity, is involved in the resection process. The Dna2 helicase activity has been implicated in Okazaki fragment processing during DNA replication but is thought to be dispensable for DNA end resection. Unexpectedly, we found a requirement for the helicase function of Dna2 in end resection in budding yeast cells lacking exonuclease 1. Biochemical analysis reveals that ATP hydrolysis-fueled translocation of Dna2 on ssDNA facilitates 5' flap cleavage near a single-strand-double strand junction while attenuating 3' flap incision...
March 23, 2017: Genes & Development
https://www.readbyqxmd.com/read/28336515/the-motor-activity-of-dna2-functions-as-an-ssdna-translocase-to-promote-dna-end-resection
#9
Maryna Levikova, Cosimo Pinto, Petr Cejka
DNA2 nuclease-helicase functions in DNA replication and recombination. This requires the nuclease of DNA2, while, in contrast, the role of the helicase activity has been unclear. We now show that the motor activity of both recombinant yeast and human DNA2 promotes efficient degradation of long stretches of ssDNA, particularly in the presence of the replication protein A. This degradation is further stimulated by a direct interaction with a cognate RecQ family helicase, which functions with DNA2 in DNA end resection to initiate homologous recombination...
March 23, 2017: Genes & Development
https://www.readbyqxmd.com/read/28404632/transcriptional-integration-of-paternal-and-maternal-factors-in-the-arabidopsis-zygote
#10
Minako Ueda, Ernst Aichinger, Wen Gong, Edwin Groot, Inge Verstraeten, Lam Dai Vu, Ive De Smet, Tetsuya Higashiyama, Masaaki Umeda, Thomas Laux
In many plants, the asymmetric division of the zygote sets up the apical-basal axis of the embryo. Unlike animals, plant zygotes are transcriptionally active, implying that plants have evolved specific mechanisms to control transcriptional activation of patterning genes in the zygote. In Arabidopsis, two pathways have been found to regulate zygote asymmetry: YODA (YDA) mitogen-activated protein kinase (MAPK) signaling, which is potentiated by sperm-delivered mRNA of the SHORT SUSPENSOR (SSP) membrane protein, and up-regulation of the patterning gene WOX8 by the WRKY2 transcription factor...
March 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28404631/regulatory-functions-and-chromatin-loading-dynamics-of-linker-histone-h1-during-endoreplication-in-drosophila
#11
Evgeniya N Andreyeva, Travis J Bernardo, Tatyana D Kolesnikova, Xingwu Lu, Lyubov A Yarinich, Boris A Bartholdy, Xiaohan Guo, Olga V Posukh, Sean Healton, Michael A Willcockson, Alexey V Pindyurin, Igor F Zhimulev, Arthur I Skoultchi, Dmitry V Fyodorov
Eukaryotic DNA replicates asynchronously, with discrete genomic loci replicating during different stages of S phase. Drosophila larval tissues undergo endoreplication without cell division, and the latest replicating regions occasionally fail to complete endoreplication, resulting in underreplicated domains of polytene chromosomes. Here we show that linker histone H1 is required for the underreplication (UR) phenomenon in Drosophila salivary glands. H1 directly interacts with the Suppressor of UR (SUUR) protein and is required for SUUR binding to chromatin in vivo...
March 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28404630/mir-424-322-503-is-a-breast-cancer-tumor-suppressor-whose-loss-promotes-resistance-to-chemotherapy
#12
Ruth Rodriguez-Barrueco, Erin A Nekritz, François Bertucci, Jiyang Yu, Felix Sanchez-Garcia, Tizita Z Zeleke, Andrej Gorbatenko, Daniel Birnbaum, Elena Ezhkova, Carlos Cordon-Cardo, Pascal Finetti, David Llobet-Navas, Jose M Silva
The female mammary gland is a very dynamic organ that undergoes continuous tissue remodeling during adulthood. Although it is well established that the number of menstrual cycles and pregnancy (in this case transiently) increase the risk of breast cancer, the reasons are unclear. Growing clinical and experimental evidence indicates that improper involution plays a role in the development of this malignancy. Recently, we described the miR-424(322)/503 cluster as an important regulator of mammary epithelial involution after pregnancy...
March 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28404629/braf-signaling-principles-unveiled-by-large-scale-human-mutation-analysis-with-a-rapid-lentivirus-based-gene-replacement-method
#13
Chae-Seok Lim, Xi Kang, Vincent Mirabella, Huaye Zhang, Qian Bu, Yoichi Araki, Elizabeth T Hoang, Shiqiang Wang, Ying Shen, Sukwoo Choi, Bong-Kiun Kaang, Qiang Chang, Zhiping P Pang, Richard L Huganir, J Julius Zhu
Rapid advances in genetics are linking mutations on genes to diseases at an exponential rate, yet characterizing the gene mutation-cell behavior relationships essential for precision medicine remains a daunting task. More than 350 mutations on small GTPase BRaf are associated with various tumors, and ∼40 mutations are associated with the neurodevelopmental disorder cardio-facio-cutaneous syndrome (CFC). We developed a fast cost-effective lentivirus-based rapid gene replacement method to interrogate the physiopathology of BRaf and ∼50 disease-linked BRaf mutants, including all CFC-linked mutants...
March 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28381412/the-ddr-at-telomeres-lacking-intact-shelterin-does-not-require-substantial-chromatin-decompaction
#14
Leonid A Timashev, Hazen Babcock, Xiaowei Zhuang, Titia de Lange
Telomeres are protected by shelterin, a six-subunit protein complex that represses the DNA damage response (DDR) at chromosome ends. Extensive data suggest that TRF2 in shelterin remodels telomeres into the t-loop structure, thereby hiding telomere ends from double-stranded break repair and ATM signaling, whereas POT1 represses ATR signaling by excluding RPA. An alternative protection mechanism was suggested recently by which shelterin subunits TRF1, TRF2, and TIN2 mediate telomeric chromatin compaction, which was proposed to minimize access of DDR factors...
March 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28381411/dual-functionality-of-cis-regulatory-elements-as-developmental-enhancers-and-polycomb-response-elements
#15
Jelena Erceg, Tibor Pakozdi, Raquel Marco-Ferreres, Yad Ghavi-Helm, Charles Girardot, Adrian P Bracken, Eileen E M Furlong
Developmental gene expression is tightly regulated through enhancer elements, which initiate dynamic spatio-temporal expression, and Polycomb response elements (PREs), which maintain stable gene silencing. These two cis-regulatory functions are thought to operate through distinct dedicated elements. By examining the occupancy of the Drosophila pleiohomeotic repressive complex (PhoRC) during embryogenesis, we revealed extensive co-occupancy at developmental enhancers. Using an established in vivo assay for PRE activity, we demonstrated that a subset of characterized developmental enhancers can function as PREs, silencing transcription in a Polycomb-dependent manner...
March 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28381410/the-telomeric-dna-damage-response-occurs-in-the-absence-of-chromatin-decompaction
#16
Aleksandra Vancevska, Kyle M Douglass, Verena Pfeiffer, Suliana Manley, Joachim Lingner
Telomeres are specialized nucleoprotein structures that protect chromosome ends from DNA damage response (DDR) and DNA rearrangements. The telomeric shelterin protein TRF2 suppresses the DDR, and this function has been attributed to its abilities to trigger t-loop formation or prevent massive decompaction and loss of density of telomeric chromatin. Here, we applied stochastic optical reconstruction microscopy (STORM) to measure the sizes and shapes of functional human telomeres of different lengths and dysfunctional telomeres that elicit a DDR...
March 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28385788/the-making-of-a-lymphocyte-the-choice-among-disparate-cell-fates-and-the-ikaros-enigma
#17
REVIEW
Katia Georgopoulos
Lymphocyte differentiation is set to produce myriad immune effector cells with the ability to respond to multitudinous foreign substances. The uniqueness of this developmental system lies in not only the great diversity of cellular functions that it can generate but also the ability of its differentiation intermediates and mature effector cells to expand upon demand, thereby providing lifelong immunity. Surprisingly, the goals of this developmental system are met by a relatively small group of DNA-binding transcription factors that work in concert to control the timing and magnitude of gene expression and fulfill the demands for cellular specialization, expansion, and maintenance...
March 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28356342/widespread-changes-in-nucleosome-accessibility-without-changes-in-nucleosome-occupancy-during-a-rapid-transcriptional-induction
#18
Britta Mueller, Jakub Mieczkowski, Sharmistha Kundu, Peggy Wang, Ruslan Sadreyev, Michael Y Tolstorukov, Robert E Kingston
Activation of transcription requires alteration of chromatin by complexes that increase the accessibility of nucleosomal DNA. Removing nucleosomes from regulatory sequences has been proposed to play a significant role in activation. We tested whether changes in nucleosome occupancy occurred on the set of genes that is activated by the unfolded protein response (UPR). We observed no decrease in occupancy on most promoters, gene bodies, and enhancers. Instead, there was an increase in the accessibility of nucleosomes, as measured by micrococcal nuclease (MNase) digestion and ATAC-seq (assay for transposase-accessible chromatin [ATAC] using sequencing), that did not result from removal of the nucleosome...
March 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28314766/the-metabolic-programming-of-stem-cells
#19
REVIEW
Ng Shyh-Chang, Huck-Hui Ng
Advances in metabolomics have deepened our understanding of the roles that specific modes of metabolism play in programming stem cell fates. Here, we review recent metabolomic studies of stem cell metabolism that have revealed how metabolic pathways can convey changes in the extrinsic environment or their niche to program stem cell fates. The metabolic programming of stem cells represents a fine balance between the intrinsic needs of a cellular state and the constraints imposed by extrinsic conditions. A more complete understanding of these needs and constraints will afford us greater mastery over our control of stem cell fates...
February 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28314765/no-back-seat-for-a-progression-event-k-ras-as-a-therapeutic-target-in-crc
#20
REVIEW
Emily J Poulin, Kevin M Haigis
KRAS is the most frequently mutated oncogene in human cancer and plays a central, although poorly understood, role in colorectal cancer (CRC) progression. In this issue of Genes & Development, Boutin and colleagues (pp. 370-382) present a new mouse model of CRC in which the expression of oncogenic K-RAS is regulated by doxycycline. Using this model, they demonstrate that continued expression of oncogenic K-RAS is required for the survival of primary and metastatic colon cancers and that oncogenic K-RAS activates TGF-β signaling to promote tumor invasion and metastasis...
February 15, 2017: Genes & Development
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