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Genes & Development

Aniek Janssen, Serafin U Colmenares, Timothy Lee, Gary H Karpen
Repair of DNA double-strand breaks (DSBs) must be orchestrated properly within diverse chromatin domains in order to maintain genetic stability. Euchromatin and heterochromatin domains display major differences in histone modifications, biophysical properties, and spatiotemporal dynamics of DSB repair. However, it is unclear whether differential histone-modifying activities are required for DSB repair in these distinct domains. We showed previously that the Drosophila melanogaster KDM4A (dKDM4A) histone demethylase is required for heterochromatic DSB mobility...
December 21, 2018: Genes & Development
Zibo Zhao, Lu Wang, Andrew G Volk, Noah W Birch, Kristen L Stoltz, Elizabeth T Bartom, Stacy A Marshall, Emily J Rendleman, Carson M Nestler, Joseph Shilati, Gary E Schiltz, John D Crispino, Ali Shilatifard
Chromosomal translocations of the Mixed-lineage leukemia 1 (MLL1) gene generate MLL chimeras that drive the pathogenesis of acute myeloid and lymphoid leukemia. The untranslocated MLL1 is a substrate for proteolytic cleavage by the endopeptidase threonine aspartase 1 (taspase1); however, the biological significance of MLL1 cleavage by this endopeptidase remains unclear. Here, we demonstrate that taspase1-dependent cleavage of MLL1 results in the destabilization of MLL. Upon loss of taspase1, MLL1 association with chromatin is markedly increased due to the stabilization of its unprocessed version, and this stabilization of the uncleaved MLL1 can result in the displacement of MLL chimeras from chromatin in leukemic cells...
December 20, 2018: Genes & Development
Kehan Bao, Chun-Min Shan, James Moresco, John Yates, Songtao Jia
Heterochromatin is a highly condensed form of chromatin that silences gene transcription. Although high levels of transcriptional activities disrupt heterochromatin, transcription of repetitive DNA elements and subsequent processing of the transcripts by the RNAi machinery are required for heterochromatin assembly. In fission yeast, a JmjC domain protein, Epe1, promotes transcription of DNA repeats to facilitate heterochromatin formation, but overexpression of Epe1 leads to heterochromatin defects. However, the molecular function of Epe1 is not well understood...
December 20, 2018: Genes & Development
David M Moquin, Marie-Michelle Genois, Jia-Min Zhang, Jian Ouyang, Tribhuwan Yadav, Rémi Buisson, Stephanie A Yazinski, Jun Tan, Myriam Boukhali, Jean-Philippe Gagné, Guy G Poirier, Li Lan, Wilhelm Haas, Lee Zou
Numerous DNA repair and signaling proteins function at DNA damage sites to protect the genome. Here, we show that fusion of the promiscuous biotin ligase BirAR118G with RAD18 leads to localized protein biotinylation at DNA damage sites, allowing identification of ZPET (zinc finger protein proximal to RAD eighteen)/ZNF280C as a potential DNA damage response (DDR) protein. ZPET binds ssDNA and localizes to DNA double-strand breaks (DSBs) and stalled replication forks. In vitro, ZPET inhibits MRE11 binding to ssDNA...
December 19, 2018: Genes & Development
Idan Cohen, Dejian Zhao, Gopinathan Menon, Manabu Nakayama, Haruhiko Koseki, Deyou Zheng, Elena Ezhkova
Polycomb-repressive complex 1 (PRC1) and PRC2 are critical chromatin regulators of gene expression and tissue development. Here, we show that despite extensive genomic cobinding, PRC1 is essential for epidermal integrity, whereas PRC2 is dispensable. Loss of PRC1 resulted in blistering skin, reminiscent of human skin fragility syndromes. Conversely, PRC1 does not restrict epidermal stratification during skin morphogenesis, whereas PRC2 does. Molecular dissection demonstrated that PRC1 functions with PRC2 to silence/dampen expression of adhesion genes...
December 19, 2018: Genes & Development
Chenchun Weng, Joanna Kosalka, Ahmet C Berkyurek, Przemyslaw Stempor, Xuezhu Feng, Hui Mao, Chenming Zeng, Wen-Jun Li, Yong-Hong Yan, Meng-Qiu Dong, Natalia Rosalía Morero, Cecilia Zuliani, Orsolya Barabas, Julie Ahringer, Shouhong Guang, Eric A Miska
Piwi-interacting RNAs (piRNAs) engage Piwi proteins to suppress transposons and nonself nucleic acids and maintain genome integrity and are essential for fertility in a variety of organisms. In Caenorhabditis elegans , most piRNA precursors are transcribed from two genomic clusters that contain thousands of individual piRNA transcription units. While a few genes have been shown to be required for piRNA biogenesis, the mechanism of piRNA transcription remains elusive. Here we used functional proteomics approaches to identify an upstream sequence transcription complex (USTC) that is essential for piRNA biogenesis...
December 19, 2018: Genes & Development
Heehwa G Son, Keunhee Seo, Mihwa Seo, Sangsoon Park, Seokjin Ham, Seon Woo A An, Eun-Seok Choi, Yujin Lee, Haeshim Baek, Eunju Kim, Youngjae Ryu, Chang Man Ha, Ao-Lin Hsu, Tae-Young Roh, Sung Key Jang, Seung-Jae V Lee
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...
November 26, 2018: Genes & Development
Martha V Koerner, Laura FitzPatrick, Jim Selfridge, Jacky Guy, Dina De Sousa, Rebekah Tillotson, Alastair Kerr, Zheng Sun, Mitchell A Lazar, Matthew J Lyst, Adrian Bird
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 equivalent high levels, was phenotypically indistinguishable from wild type, suggesting that excessive corepressor recruitment underlies toxicity...
November 21, 2018: Genes & Development
Madhwesh C Ravichandran, Sarah Fink, Matthew N Clarke, Franziska Christina Hofer, Christopher S Campbell
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...
November 21, 2018: Genes & Development
Héloïse Coutelier, Zhou Xu, Mony Chenda Morisse, Maoussi Lhuillier-Akakpo, Serge Pelet, Gilles Charvin, Karine Dubrana, Maria Teresa Teixeira
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 imaging in yeast...
November 21, 2018: Genes & Development
Hideyuki Komori, Krista L Golden, Taeko Kobayashi, Ryoichiro Kageyama, Cheng-Yu Lee
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 neural stem cell lineage...
November 21, 2018: Genes & Development
Azusa Inoue, Zhiyuan Chen, Qiangzong Yin, Yi Zhang
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...
November 21, 2018: Genes & Development
Nozomi Takahashi, Andrea Coluccio, Christian W Thorball, Evarist Planet, Hui Shi, Sandra Offner, Priscilla Turelli, Michael Imbeault, Anne C Ferguson-Smith, Didier Trono
Genomic imprinting is an epigenetic process regulated by germline-derived DNA methylation, causing parental origin-specific monoallelic gene expression. Zinc finger protein 57 (ZFP57) is critical for maintenance of this epigenetic memory during post-fertilization reprogramming, yet incomplete penetrance of ZFP57 mutations in humans and mice suggests additional effectors. We reveal that ZNF445/ZFP445, which we trace to the origins of imprinting, binds imprinting control regions (ICRs) in mice and humans. In mice, ZFP445 and ZFP57 act together, maintaining all but one ICR in vivo, whereas earlier embryonic expression of ZNF445 and its intolerance to loss-of-function mutations indicate greater importance in the maintenance of human imprints...
January 1, 2019: Genes & Development
Mark R Boothby, Emily Hodges, James W Thomas
Mature B lymphocytes are crucial components of adaptive immunity, a system essential for the evolutionary fitness of mammals. Adaptive lymphocyte function requires an initially naïve cell to proliferate extensively and its progeny to have the capacity to assume a variety of fates. These include either terminal differentiation (the long-lived plasma cell) or metastable transcriptional reprogramming (germinal center and memory B cells). In this review, we focus principally on the regulation of differentiation and functional diversification of the "B2" subset...
January 1, 2019: Genes & Development
Cornelis Murre
Helix-loop-helix (HLH) proteins are dimeric transcription factors that control lineage- and developmental-specific gene programs. Genes encoding for HLH proteins arose in unicellular organisms >600 million years ago and then duplicated and diversified from ancestral genes across the metazoan and plant kingdoms to establish multicellularity. Hundreds of HLH proteins have been identified with diverse functions in a wide variety of cell types. HLH proteins orchestrate lineage specification, commitment, self-renewal, proliferation, differentiation, and homing...
January 1, 2019: Genes & Development
Dongmei Wang, Rui Yi
All of the cells in our body share largely identical DNA, yet functionally distinct cells are generated to give rise to different tissues and organs. A fundamental question in biology is how different cell fates are specified and maintained. Epigenetic mechanisms hold a key answer to the question. Without changing the sequence of DNA but through modifying DNA, histones, or RNA, epigenetic mechanisms can decide which genes to express and which to suppress. Polycomb group (PcG) proteins are a group of evolutionarily conserved proteins that can regulate gene expression through histone modification...
January 1, 2019: Genes & Development
Aimee M Juan, Marisa S Bartolomei
The monoallelic parent of origin-specific expression of imprinted genes in mammals is regulated by differentially DNA methylated imprinting control regions (ICRs). In contrast to most of the genome, ICRs must maintain their DNA methylation and parental identity despite extensive epigenetic reprogramming that takes place after fertilization. Previous work demonstrated that the Krüppel-associated box (KRAB)-containing zinc finger protein (KZFP) ZFP57 protects select ICRs from demethylation and preserves parental identity...
January 1, 2019: Genes & Development
(no author information available yet)
No abstract text is available yet for this article.
December 1, 2018: Genes & Development
Ran Wei, Lily Wen Xu, Jianping Liu, Yanxia Li, Pei Zhang, Bing Shan, Xiaojuan Lu, Lihui Qian, Zheming Wu, Kangyun Dong, Hong Zhu, Lifeng Pan, Junying Yuan, Heling Pan
No abstract text is available yet for this article.
December 1, 2018: Genes & Development
John P Leach, Edward E Morrisey
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...
December 1, 2018: Genes & Development
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