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Genes & Development

Charles Ng, Martin Aichinger, Tung Nguyen, Christy Au, Tariq Najar, Lin Wu, Kai R Mesa, Will Liao, Jean-Pierre Quivy, Benjamin Hubert, Genevieve Almouzni, Johannes Zuber, Dan R Littman
The transcriptional repression of alternative lineage genes is critical for cell fate commitment. Mechanisms by which locus-specific gene silencing is initiated and heritably maintained during cell division are not clearly understood. To study the maintenance of silent gene states, we investigated how the Cd4 gene is stably repressed in CD8+ T cells. Through CRISPR and shRNA screening, we identified the histone chaperone CAF-1 as a critical component for Cd4 repression. We found that the large subunit of CAF-1, Chaf1a, requires the N-terminal KER domain to associate with the histone deacetylases HDAC1/2 and the histone demethylase LSD1, enzymes that also participate in Cd4 silencing...
April 11, 2019: Genes & Development
Stephen Li, Kenian Chen, Yichi Zhang, Spencer D Barnes, Priscilla Jaichander, Yanbin Zheng, Mohammed Hassan, Venkat S Malladi, Stephen X Skapek, Lin Xu, Rhonda Bassel-Duby, Eric N Olson, Ning Liu
Rhabdomyosarcoma (RMS) is an aggressive pediatric cancer composed of myoblast-like cells. Recently, we discovered a unique muscle progenitor marked by the expression of the Twist2 transcription factor. Genomic analyses of 258 RMS patient tumors uncovered prevalent copy number amplification events and increased expression of TWIST2 in fusion-negative RMS. Knockdown of TWIST2 in RMS cells results in up-regulation of MYOGENIN and a decrease in proliferation, implicating TWIST2 as an oncogene in RMS. Through an inducible Twist2 expression system, we identified Twist2 as a reversible inhibitor of myogenic differentiation with the remarkable ability to promote myotube dedifferentiation in vitro...
April 11, 2019: Genes & Development
Victoria Dorich, Christiane Brugger, Arti Tripathi, Joel R Hoskins, Song Tong, Margaret M Suhanovsky, Amita Sastry, Sue Wickner, Susan Gottesman, Alexandra M Deaconescu
The stationary phase promoter specificity subunit σS (RpoS) is delivered to the ClpXP machinery for degradation dependent on the adaptor RssB. This adaptor-specific degradation of σS provides a major point for regulation and transcriptional reprogramming during the general stress response. RssB is an atypical response regulator and the only known ClpXP adaptor that is inhibited by multiple but dissimilar antiadaptors (IraD, IraP, and IraM). These are induced by distinct stress signals and bind to RssB in poorly understood manners to achieve stress-specific inhibition of σS turnover...
April 11, 2019: Genes & Development
Haoyang Jiang, Marley Wolgast, Laura M Beebe, Joseph C Reese
The Ccr4-Not complex regulates essentially every aspect of gene expression, from mRNA synthesis to protein destruction. The Not4 subunit of the complex contains an E3 RING domain and targets proteins for ubiquitin-dependent proteolysis. Ccr4-Not associates with elongating RNA polymerase II (RNAPII), which raises the possibility that it controls the degradation of elongation complex components. Here, we demonstrate that Ccr4-Not controls the ubiquitylation and turnover of Rpb1, the largest subunit of RNAPII, during transcription arrest...
April 4, 2019: Genes & Development
Daniel T Swarr, Michael Herriges, Shanru Li, Mike Morley, Sharlene Fernandes, Anusha Sridharan, Su Zhou, Benjamin A Garcia, Kathleen Stewart, Edward E Morrisey
Transcription factors (TFs) are dosage-sensitive master regulators of gene expression, with haploinsufficiency frequently leading to life-threatening disease. Numerous mechanisms have evolved to tightly regulate the expression and activity of TFs at the transcriptional, translational, and posttranslational levels. A subset of long noncoding RNAs (lncRNAs) is spatially correlated with transcription factors in the genome, but the regulatory relationship between these lncRNAs and their neighboring TFs is unclear...
March 28, 2019: Genes & Development
Seongmin Jang, Chanshin Kang, Han-Sol Yang, Taeyang Jung, Hans Hebert, Ka Young Chung, Seung Joong Kim, Sungchul Hohng, Ji-Joon Song
DOT1L is a histone H3 Lys79 methyltransferase whose activity is stimulated by histone H2B Lys120 ubiquitination, suggesting cross-talk between histone H3 methylation and H2B ubiquitination. Here, we present cryo-EM structures of DOT1L complexes with unmodified or H2B ubiquitinated nucleosomes, showing that DOT1L recognizes H2B ubiquitin and the H2A/H2B acidic patch through a C-terminal hydrophobic helix and an arginine anchor in DOT1L, respectively. Furthermore, the structures combined with single-molecule FRET experiments show that H2B ubiquitination enhances a noncatalytic function of the DOT1L-destabilizing nucleosome...
March 28, 2019: Genes & Development
Risa Sueda, Itaru Imayoshi, Yukiko Harima, Ryoichiro Kageyama
Somatic stem/progenitor cells are active in embryonic tissues but quiescent in many adult tissues. The detailed mechanisms that regulate active versus quiescent stem cell states are largely unknown. In active neural stem cells, Hes1 expression oscillates and drives cyclic expression of the proneural gene Ascl1 , which activates cell proliferation. Here, we found that in quiescent neural stem cells in the adult mouse brain, Hes1 levels are oscillatory, although the peaks and troughs are higher than those in active neural stem cells, causing Ascl1 expression to be continuously suppressed...
March 12, 2019: Genes & Development
Ines Lahmann, Dominique Bröhl, Tatiana Zyrianova, Akihiro Isomura, Maciej T Czajkowski, Varun Kapoor, Joscha Griger, Pierre-Louis Ruffault, Despoina Mademtzoglou, Peter S Zammit, Thomas Wunderlich, Simone Spuler, Ralf Kühn, Stephan Preibisch, Jana Wolf, Ryoichiro Kageyama, Carmen Birchmeier
The balance between proliferation and differentiation of muscle stem cells is tightly controlled, ensuring the maintenance of a cellular pool needed for muscle growth and repair. We demonstrate here that the transcriptional regulator Hes1 controls the balance between proliferation and differentiation of activated muscle stem cells in both developing and regenerating muscle. We observed that Hes1 is expressed in an oscillatory manner in activated stem cells where it drives the oscillatory expression of MyoD...
March 12, 2019: Genes & Development
Yoo Jin Joo, Scott B Ficarro, Yujin Chun, Jarrod A Marto, Stephen Buratowski
RNA polymerase II elongation complexes (ECs) were assembled from nuclear extract on immobilized DNA templates and analyzed by quantitative mass spectrometry. Time-course experiments showed that initiation factor TFIIF can remain bound to early ECs, while levels of core elongation factors Spt4-Spt5, Paf1C, Spt6-Spn1, and Elf1 remain steady. Importantly, the dynamic phosphorylation patterns of the Rpb1 C-terminal domain (CTD) and the factors that recognize them change as a function of postinitiation time rather than distance elongated...
March 7, 2019: Genes & Development
Murali Palangat, Dimitrios G Anastasakis, Dennis Liang Fei, Katherine E Lindblad, Robert Bradley, Christopher S Hourigan, Markus Hafner, Daniel R Larson
Somatic mutations in the genes encoding components of the spliceosome occur frequently in human neoplasms, including myeloid dysplasias and leukemias, and less often in solid tumors. One of the affected factors, U2AF1, is involved in splice site selection, and the most common change, S34F, alters a conserved nucleic acid-binding domain, recognition of the 3' splice site, and alternative splicing of many mRNAs. However, the role that this mutation plays in oncogenesis is still unknown. Here, we uncovered a noncanonical function of U2AF1, showing that it directly binds mature mRNA in the cytoplasm and negatively regulates mRNA translation...
March 6, 2019: Genes & Development
Jianshu Wang, Jiyun Chen, Guifen Wu, Hongling Zhang, Xian Du, Suli Chen, Li Zhang, Ke Wang, Jing Fan, Shuaixin Gao, Xudong Wu, Shouxiang Zhang, Bin Kuai, Peng Zhao, Binkai Chi, Lantian Wang, Guohui Li, Catherine C L Wong, Yu Zhou, Jinsong Li, Caihong Yun, Hong Cheng
The exosome functions in the degradation of diverse RNA species, yet how it is negatively regulated remains largely unknown. Here, we show that NRDE2 forms a 1:1 complex with MTR4, a nuclear exosome cofactor critical for exosome recruitment, via a conserved MTR4-interacting domain (MID). Unexpectedly, NRDE2 mainly localizes in nuclear speckles, where it inhibits MTR4 recruitment and RNA degradation, and thereby ensures efficient mRNA nuclear export. Structural and biochemical data revealed that NRDE2 interacts with MTR4's key residues, locks MTR4 in a closed conformation, and inhibits MTR4 interaction with the exosome as well as proteins important for MTR4 recruitment, such as the cap-binding complex (CBC) and ZFC3H1...
March 6, 2019: Genes & Development
Rupam Choudhury, Sukhdeep Singh, Senthil Arumugam, Assen Roguev, A Francis Stewart
Epigenetic modifications can maintain or alter the inherent symmetry of the nucleosome. However, the mechanisms that deposit and/or propagate symmetry or asymmetry are not understood. Here we report that yeast Set1C/COMPASS (complex of proteins associated with Set1) is dimeric and, consequently, symmetrically trimethylates histone 3 Lys4 (H3K4me3) on promoter nucleosomes. Mutation of the dimer interface to make Set1C monomeric abolished H3K4me3 on most promoters. The most active promoters, particularly those involved in the oxidative phase of the yeast metabolic cycle, displayed H3K4me2, which is normally excluded from active promoters, and a subset of these also displayed H3K4me3...
March 6, 2019: Genes & Development
Nishani Rajakulendran, Katherine J Rowland, Hayden J Selvadurai, Moloud Ahmadi, Nicole I Park, Sergey Naumenko, Sonam Dolma, Ryan J Ward, Milly So, Lilian Lee, Graham MacLeod, Clarissa Pasiliao, Caroline Brandon, Ian D Clarke, Michael D Cusimano, Mark Bernstein, Nizar Batada, Stephane Angers, Peter B Dirks
Developmental signal transduction pathways act diversely, with context-dependent roles across systems and disease types. Glioblastomas (GBMs), which are the poorest prognosis primary brain cancers, strongly resemble developmental systems, but these growth processes have not been exploited therapeutically, likely in part due to the extreme cellular and genetic heterogeneity observed in these tumors. The role of Wnt/βcatenin signaling in GBM stem cell (GSC) renewal and fate decisions remains controversial. Here, we report context-specific actions of Wnt/βcatenin signaling in directing cellular fate specification and renewal...
March 6, 2019: Genes & Development
Seung H Choi, Thomas F Martinez, Seongjae Kim, Cynthia Donaldson, Maxim N Shokhirev, Alan Saghatelian, Katherine A Jones
The RNA polymerase II (RNAPII) C-terminal domain kinase, CDK12, regulates genome stability, expression of DNA repair genes, and cancer cell resistance to chemotherapy and immunotherapy. In addition to its role in mRNA biosynthesis of DNA repair genes, we show here that CDK12 phosphorylates the mRNA 5' cap-binding repressor, 4E-BP1, to promote translation of mTORC1-dependent mRNAs. In particular, we found that phosphorylation of 4E-BP1 by mTORC1 (T37 and T46) facilitates subsequent CDK12 phosphorylation at two Ser-Pro sites (S65 and T70) that control the exchange of 4E-BP1 with eIF4G at the 5' cap of CHK1 and other target mRNAs...
February 28, 2019: Genes & Development
Kin Chung Lam, Ho-Ryun Chung, Giuseppe Semplicio, Shantanu S Iyer, Aline Gaub, Vivek Bhardwaj, Herbert Holz, Plamen Georgiev, Asifa Akhtar
Nucleosomal organization at gene promoters is critical for transcription, with a nucleosome-depleted region (NDR) at transcription start sites (TSSs) being required for transcription initiation. How NDRs and the precise positioning of the +1 nucleosomes are maintained on active genes remains unclear. Here, we report that the Drosophila nonspecific lethal (NSL) complex is necessary to maintain this stereotypical nucleosomal organization at promoters. Upon NSL1 depletion, nucleosomes invade the NDRs at TSSs of NSL-bound genes...
February 28, 2019: Genes & Development
Wenhao Zhang, Zhiyuan Chen, Qiangzong Yin, Dan Zhang, Catherine Racowsky, Yi Zhang
Genomic imprinting is an epigenetic mechanism by which genes are expressed in a parental origin-dependent manner. We recently discovered that, like DNA methylation, oocyte-inherited H3K27me3 can also serve as an imprinting mark in mouse preimplantation embryos. In this study, we found H3K27me3 is strongly biased toward the maternal allele with some associated with DNA methylation-independent paternally expressed genes (PEGs) in human morulae. The H3K27me3 domains largely overlap with DNA partially methylated domains (PMDs) and occupy developmental gene promoters...
February 26, 2019: Genes & Development
Anant Shah, Tiffany A Melhuish, Todd E Fox, Henry F Frierson, David Wotton
Tgif1 (thymine-guanine-interacting factor 1) and Tgif2 repress gene expression by binding directly to DNA or interacting with transforming growth factor (TGF) β-responsive SMADs. Tgifs are essential for embryogenesis and may function in tumor progression. By analyzing both gain and loss of Tgif function in a well-established mouse model of intestinal cancer, we show that Tgifs promote adenoma growth in the context of mutant Apc ( adenomatous polyposis coli ). Despite the tumor-suppressive role of TGFβ signaling, transcriptome profiling of colon tumors suggests minimal effect of Tgifs on the TGFβ pathway...
February 26, 2019: Genes & Development
Charles A Seller, Chun-Yi Cho, Patrick H O'Farrell
Acquisition of chromatin modifications during embryogenesis distinguishes different regions of an initially naïve genome. In many organisms, repetitive DNA is packaged into constitutive heterochromatin that is marked by di/trimethylation of histone H3K9 and the associated protein HP1a. These modifications enforce the unique epigenetic properties of heterochromatin. However, in the early Drosophila melanogaster embryo, the heterochromatin lacks these modifications, which appear only later, when rapid embryonic cell cycles slow down at the midblastula transition (MBT)...
February 26, 2019: Genes & Development
Xiaolu Zhao, Jie Xiong, Fengbiao Mao, Yalan Sheng, Xiao Chen, Lifang Feng, Wen Dui, Wentao Yang, Aurélie Kapusta, Cédric Feschotte, Robert S Coyne, Wei Miao, Shan Gao, Yifan Liu
RNAi and Polycomb repression play evolutionarily conserved and often coordinated roles in transcriptional silencing. Here, we show that, in the protozoan Tetrahymena thermophila , germline-specific internally eliminated sequences (IESs)-many related to transposable elements (TEs)-become transcriptionally activated in mutants deficient in the RNAi-dependent Polycomb repression pathway. Germline TE mobilization also dramatically increases in these mutants. The transition from noncoding RNA (ncRNA) to mRNA production accompanies transcriptional activation of TE-related sequences and vice versa for transcriptional silencing...
February 26, 2019: Genes & Development
Karoline Leopold, Alessandro Stirpe, Thomas Schalch
Heterochromatin protein 1 (HP1) proteins are key factors of eukaryotic heterochromatin that coordinate chromatin compaction and transcriptional gene silencing. Through their multivalency they act as adaptors between histone H3 Lys9 di/trimethyl marks in chromatin and effector complexes that bind to the HP1 chromoshadow domain. Most organisms encode for multiple HP1 isoforms and the molecular mechanisms that underpin their diverse functions in genome regulation remain poorly understood. In fission yeast, the two HP1 proteins Chp2 and Swi6 assume distinct roles and Chp2 is tightly associated with the nucleosome remodeling and deacetylation complex SHREC...
February 26, 2019: Genes & Development
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