A single-cell atlas of the developing Drosophila ovary identifies follicle stem cell progenitors [Resource/Methodology]
Addressing the complexity of organogenesis at a system-wide level requires a complete understanding of adult cell types, their origin, and precursor relationships. The Drosophila ovary has been a model to study how coordinated stem cell units, germline, and somatic follicle stem cells maintain and renew an organ. However, lack of cell type-specific tools have limited our ability to study the origin of individual cell types and stem cell units. Here, we used a single-cell RNA sequencing approach to uncover all known cell types of the developing ovary, reveal transcriptional signatures, and identify cell type-specific marker...
Source: Genes and Development - February 3, 2020 Category: Genetics & Stem Cells Authors: Slaidina, M., Banisch, T. U., Gupta, S., Lehmann, R. Tags: Resource/Methodology Source Type: research

Hap2-Ino80-facilitated transcription promotes de novo establishment of CENP-A chromatin [Research Papers]
Centromeres are maintained epigenetically by the presence of CENP-A, an evolutionarily conserved histone H3 variant, which directs kinetochore assembly and hence centromere function. To identify factors that promote assembly of CENP-A chromatin, we affinity-selected solubilized fission yeast CENP-ACnp1 chromatin. All subunits of the Ino80 complex were enriched, including the auxiliary subunit Hap2. Chromatin association of Hap2 is Ies4-dependent. In addition to a role in maintenance of CENP-ACnp1 chromatin integrity at endogenous centromeres, Hap2 is required for de novo assembly of CENP-ACnp1 chromatin on naìˆve centrome...
Source: Genes and Development - February 3, 2020 Category: Genetics & Stem Cells Authors: Singh, P. P., Shukla, M., White, S. A., Lafos, M., Tong, P., Auchynnikava, T., Spanos, C., Rappsilber, J., Pidoux, A. L., Allshire, R. C. Tags: Research Papers Source Type: research

Aurora B-dependent Ndc80 degradation regulates kinetochore composition in meiosis [Research Papers]
The kinetochore complex is a conserved machinery that connects chromosomes to spindle microtubules. During meiosis, the kinetochore is restructured to accommodate a specialized chromosome segregation pattern. In budding yeast, meiotic kinetochore remodeling is mediated by the temporal changes in the abundance of a single subunit called Ndc80. We previously described the regulatory events that control the timely synthesis of Ndc80. Here, we report that Ndc80 turnover is also tightly regulated in meiosis: Ndc80 degradation is active in meiotic prophase, but not in metaphase I. Ndc80 degradation depends on the ubiquitin ligas...
Source: Genes and Development - February 3, 2020 Category: Genetics & Stem Cells Authors: Chen, J., Liao, A., Powers, E. N., Liao, H., Kohlstaedt, L. A., Evans, R., Holly, R. M., Kim, J. K., Jovanovic, M., Ünal, E. Tags: Research Papers Source Type: research

The microtubule regulator ringer functions downstream from the RNA repair/splicing pathway to promote axon regeneration [Research Papers]
Promoting axon regeneration in the central and peripheral nervous system is of clinical importance in neural injury and neurodegenerative diseases. Both pro- and antiregeneration factors are being identified. We previously reported that the Rtca mediated RNA repair/splicing pathway restricts axon regeneration by inhibiting the nonconventional splicing of Xbp1 mRNA under cellular stress. However, the downstream effectors remain unknown. Here, through transcriptome profiling, we show that the tubulin polymerization-promoting protein (TPPP) ringmaker/ringer is dramatically increased in Rtca-deficient Drosophila sensory neuron...
Source: Genes and Development - February 3, 2020 Category: Genetics & Stem Cells Authors: Vargas, E. J. M., Matamoros, A. J., Qiu, J., Jan, C. H., Wang, Q., Gorczyca, D., Han, T. W., Weissman, J. S., Jan, Y. N., Banerjee, S., Song, Y. Tags: Research Papers Source Type: research

TRPS1 acts as a context-dependent regulator of mammary epithelial cell growth/differentiation and breast cancer development [Research Papers]
The GATA-type zinc finger transcription factor TRPS1 has been implicated in breast cancer. However, its precise role remains unclear, as both amplifications and inactivating mutations in TRPS1 have been reported. Here, we used in vitro and in vivo loss-of-function approaches to dissect the role of TRPS1 in mammary gland development and invasive lobular breast carcinoma, which is hallmarked by functional loss of E-cadherin. We show that TRPS1 is essential in mammary epithelial cells, since TRPS1-mediated suppression of interferon signaling promotes in vitro proliferation and lactogenic differentiation. Similarly, TRPS1 expr...
Source: Genes and Development - February 3, 2020 Category: Genetics & Stem Cells Authors: Cornelissen, L. M., Drenth, A. P., van der Burg, E., de Bruijn, R., Pritchard, C. E. J., Huijbers, I. J., Zwart, W., Jonkers, J. Tags: Research Papers Source Type: research

The chromatin remodeler Snf2h is essential for oocyte meiotic cell cycle progression [Research Papers]
Oocytes are indispensable for mammalian life. Thus, it is important to understand how mature oocytes are generated. As a critical stage of oocytes development, meiosis has been extensively studied, yet how chromatin remodeling contributes to this process is largely unknown. Here, we demonstrate that the ATP-dependent chromatin remodeling factor Snf2h (also known as Smarca5) plays a critical role in regulating meiotic cell cycle progression. Females with oocyte-specific depletion of Snf2h are infertile and oocytes lacking Snf2h fail to undergo meiotic resumption. Mechanistically, depletion of Snf2h results in dysregulation ...
Source: Genes and Development - February 3, 2020 Category: Genetics & Stem Cells Authors: Zhang, C., Chen, Z., Yin, Q., Fu, X., Li, Y., Stopka, T., Skoultchi, A. I., Zhang, Y. Tags: Research Papers Source Type: research

Upon microbial challenge, human neutrophils undergo rapid changes in nuclear architecture and chromatin folding to orchestrate an immediate inflammatory gene program [Research Papers]
Differentiating neutrophils undergo large-scale changes in nuclear morphology. How such alterations in structure are established and modulated upon exposure to microbial agents is largely unknown. Here, we found that prior to encounter with bacteria, an armamentarium of inflammatory genes was positioned in a transcriptionally passive environment suppressing premature transcriptional activation. Upon microbial exposure, however, human neutrophils rapidly (
Source: Genes and Development - February 3, 2020 Category: Genetics & Stem Cells Authors: Denholtz, M., Zhu, Y., He, Z., Lu, H., Isoda, T., Döhrmann, S., Nizet, V., Murre, C. Tags: Research Papers Source Type: research

Better safe than sorry--preventing mitotic segregation of meiotic chromosomes [Outlook]
The distinctive segregation patterns of chromosomes in mitosis and meiosis are dictated in part by the kinetochores, the structures on chromosomes that attach them to the microtubules of the spindle. Inappropriate mitosis-like chromosome segregation in meiosis leads to gametes with incorrect chromosome numbers. New findings by Chen and colleagues (pp. 209–225) in this issue of Genes & Development reveal how cells restructure their kinetochores when they enter meiosis. Their results describe an interconnected set of mechanisms that provides multiple layers of protection from the carryover of mitotic chromosome seg...
Source: Genes and Development - February 3, 2020 Category: Genetics & Stem Cells Authors: Meyer, R. E., Dawson, D. S. Tags: Cell Biology, Cell Cycle and DNA Replication Outlook Source Type: research

Corrigendum: DNA polymerase {theta} accomplishes translesion synthesis opposite 1,N6-ethenodeoxyadenosine with a remarkably high fidelity in human cells [Errata]
(Source: Genes and Development)
Source: Genes and Development - January 2, 2020 Category: Genetics & Stem Cells Authors: Yoon, J.-H., Johnson, R. E., Prakash, L., Prakash, S. Tags: Errata Source Type: research

A unified allosteric/torpedo mechanism for transcriptional termination on human protein-coding genes [Research Papers]
The allosteric and torpedo models have been used for 30 yr to explain how transcription terminates on protein-coding genes. The former invokes termination via conformational changes in the transcription complex and the latter proposes that degradation of the downstream product of poly(A) signal (PAS) processing is important. Here, we describe a single mechanism incorporating features of both models. We show that termination is completely abolished by rapid elimination of CPSF73, which causes very extensive transcriptional readthrough genome-wide. This is because CPSF73 functions upstream of modifications to the elongation ...
Source: Genes and Development - January 2, 2020 Category: Genetics & Stem Cells Authors: Eaton, J. D., Francis, L., Davidson, L., West, S. Tags: Research Papers Source Type: research

Control of noncoding RNA production and histone levels by a 5' tRNA fragment [Research Papers]
Small RNAs derived from mature tRNAs, referred to as tRNA fragments or "tRFs," are an emerging class of regulatory RNAs with poorly understood functions. We recently identified a role for one specific tRF—5' tRF-Gly-GCC, or tRF-GG—as a repressor of genes associated with the endogenous retroelement MERVL, but the mechanistic basis for this regulation was unknown. Here, we show that tRF-GG plays a role in production of a wide variety of noncoding RNAs—snoRNAs, scaRNAs, and snRNAs—that are dependent on Cajal bodies for stability and activity. Among these noncoding RNAs, regulation of the U7 s...
Source: Genes and Development - January 2, 2020 Category: Genetics & Stem Cells Authors: Boskovic, A., Bing, X. Y., Kaymak, E., Rando, O. J. Tags: Research Papers Source Type: research

Set1/COMPASS repels heterochromatin invasion at euchromatic sites by disrupting Suv39/Clr4 activity and nucleosome stability [Research Papers]
Protection of euchromatin from invasion by gene-repressive heterochromatin is critical for cellular health and viability. In addition to constitutive loci such as pericentromeres and subtelomeres, heterochromatin can be found interspersed in gene-rich euchromatin, where it regulates gene expression pertinent to cell fate. While heterochromatin and euchromatin are globally poised for mutual antagonism, the mechanisms underlying precise spatial encoding of heterochromatin containment within euchromatic sites remain opaque. We investigated ectopic heterochromatin invasion by manipulating the fission yeast mating type locus bo...
Source: Genes and Development - January 2, 2020 Category: Genetics & Stem Cells Authors: Greenstein, R. A., Barrales, R. R., Sanchez, N. A., Bisanz, J. E., Braun, S., Al-Sady, B. Tags: Research Papers Source Type: research

Fork pausing complex engages topoisomerases at the replisome [Research Papers]
Replication forks temporarily or terminally pause at hundreds of hard-to-replicate regions around the genome. A conserved pair of budding yeast replisome components Tof1–Csm3 (fission yeast Swi1–Swi3 and human TIMELESS–TIPIN) act as a "molecular brake" and promote fork slowdown at proteinaceous replication fork barriers (RFBs), while the accessory helicase Rrm3 assists the replisome in removing protein obstacles. Here we show that the Tof1–Csm3 complex promotes fork pausing independently of Rrm3 helicase by recruiting topoisomerase I (Top1) to the replisome. Topoisomerase II (Top2) partial...
Source: Genes and Development - January 2, 2020 Category: Genetics & Stem Cells Authors: Shyian, M., Albert, B., Zupan, A. M., Ivanitsa, V., Charbonnet, G., Dilg, D., Shore, D. Tags: Research Papers Source Type: research

Induction of AP-1 by YAP/TAZ contributes to cell proliferation and organ growth [Research Papers]
Yes-associated protein (YAP) and its homolog transcriptional coactivator with PDZ-binding motif (TAZ) are key effectors of the Hippo pathway to control cell growth and organ size, of which dysregulation yields to tumorigenesis or hypertrophy. Upon activation, YAP/TAZ translocate into the nucleus and bind to TEAD transcription factors to promote transcriptional programs for proliferation or cell specification. Immediate early genes, represented by AP-1 complex, are rapidly induced and control later-phase transcriptional program to play key roles in tumorigenesis and organ maintenance. Here, we report that YAP/TAZ directly p...
Source: Genes and Development - January 2, 2020 Category: Genetics & Stem Cells Authors: Koo, J. H., Plouffe, S. W., Meng, Z., Lee, D.-H., Yang, D., Lim, D.-S., Wang, C.-Y., Guan, K.-L. Tags: Research Papers Source Type: research

CDK7 regulates organ size and tumor growth by safeguarding the Hippo pathway effector Yki/Yap/Taz in the nucleus [Research Papers]
Hippo signaling controls organ size and tumor progression through a conserved pathway leading to nuclear translocation of the transcriptional effector Yki/Yap/Taz. Most of our understanding of Hippo signaling pertains to its cytoplasmic regulation, but how the pathway is controlled in the nucleus remains poorly understood. Here we uncover an evolutionarily conserved mechanism by which CDK7 promotes Yki/Yap/Taz stabilization in the nucleus to sustain Hippo pathway outputs. We found that a modular E3 ubiquitin ligase complex CRL4DCAF12 binds and targets Yki/Yap/Taz for ubiquitination and degradation, whereas CDK7 phosphoryla...
Source: Genes and Development - January 2, 2020 Category: Genetics & Stem Cells Authors: Cho, Y. S., Li, S., Wang, X., Zhu, J., Zhuo, S., Han, Y., Yue, T., Yang, Y., Jiang, J. Tags: Research Papers Source Type: research

Muscle-derived Dpp regulates feeding initiation via endocrine modulation of brain dopamine biosynthesis [Research Papers]
In animals, the brain regulates feeding behavior in response to local energy demands of peripheral tissues, which secrete orexigenic and anorexigenic hormones. Although skeletal muscle is a key peripheral tissue, it remains unknown whether muscle-secreted hormones regulate feeding. In Drosophila, we found that decapentaplegic (dpp), the homolog of human bone morphogenetic proteins BMP2 and BMP4, is a muscle-secreted factor (a myokine) that is induced by nutrient sensing and that circulates and signals to the brain. Muscle-restricted dpp RNAi promotes foraging and feeding initiation, whereas dpp overexpression reduces it. T...
Source: Genes and Development - January 2, 2020 Category: Genetics & Stem Cells Authors: Robles-Murguia, M., Rao, D., Finkelstein, D., Xu, B., Fan, Y., Demontis, F. Tags: Research Papers Source Type: research

Genomic imprinting in plants--revisiting existing models [Reviews]
Genomic imprinting is an epigenetic phenomenon leading to parentally biased gene expression. Throughout the years, extensive efforts have been made to characterize the epigenetic marks underlying imprinting in animals and plants. As a result, DNA methylation asymmetries between parental genomes emerged as the primary factor controlling the imprinting status of many genes. Nevertheless, the data accumulated so far suggest that this process cannot solely explain the imprinting of all genes. In this review, we revisit the current models explaining imprinting regulation in plants, and discuss novel regulatory mechanisms that c...
Source: Genes and Development - January 2, 2020 Category: Genetics & Stem Cells Authors: Batista, R. A., Köhler, C. Tags: Plant Biology, Chromatin and Gene Expression Reviews Source Type: research

53BP1: a DSB escort [Reviews]
53BP1 is an enigmatic DNA damage response factor that gained prominence because it determines the efficacy of PARP1 inhibitory drugs (PARPi) in BRCA1-deficient cancers. Recent studies have elevated 53BP1 from its modest status of (yet another) DNA damage factor to master regulator of double-strand break (DSB) repair pathway choice. Our review of the literature suggests an alternative view. We propose that 53BP1 has evolved to avoid mutagenic repair outcomes and does so by controlling the processing of DNA ends and the dynamics of DSBs. The consequences of 53BP1 deficiency, such as diminished PARPi efficacy in BRCA1-deficie...
Source: Genes and Development - January 2, 2020 Category: Genetics & Stem Cells Authors: Mirman, Z., de Lange, T. Tags: DNA Recombination and Repair Reviews Source Type: research

Linking cancer transcriptional addictions by CDK7 to YAP/TAZ [Outlook]
Inhibition of CDK7 is a promising strategy for cancer therapy. CDK7 so far has been understood mainly in the context of Pol II-driven transcription. However, how are the roles of CDK7 in the "basal" transcriptional machinery reconciled with the function of CDK7 as inducer of specific transcriptional programs in tumor cells? In this issue of Genes & Development, Cho and colleagues (pp. 53–71) advance in this direction, demonstrating that attenuation of CDK7 fosters the oncogenic activity of the YAP/TAZ/Yki coactivators. CDK7 directly phosphorylates YAP/TAZ/Yki in the nucleus, protecting them from ubiquit...
Source: Genes and Development - January 2, 2020 Category: Genetics & Stem Cells Authors: Piccolo, S. Tags: Chromatin and Gene Expression Outlook Source Type: research

Top1 and Top2 promote replication fork arrest at a programmed pause site [Outlook]
Programmed fork pausing is a complex process allowing cells to arrest replication forks at specific loci in a polar manner. Studies in budding yeast and other model organisms indicate that such replication fork barriers do not act as roadblocks passively impeding fork progression but rather elicit complex interactions between fork and barrier components. In this issue of Genes & Development, Shyian and colleagues (pp. 87–98) show that in budding yeast, the fork protection complex Tof1–Csm3 interacts physically with DNA topoisomerase I (Top1) at replication forks through the C-terminal domain of Tof1. Fork p...
Source: Genes and Development - January 2, 2020 Category: Genetics & Stem Cells Authors: Larcher, M. V., Pasero, P. Tags: DNA Recombination and Repair Outlook Source Type: research

Reviewers, Volume 33 (2019) [Reviewers]
(Source: Genes and Development)
Source: Genes and Development - December 2, 2019 Category: Genetics & Stem Cells Tags: Reviewers Source Type: research

Systematic bromodomain protein screens identify homologous recombination and R-loop suppression pathways involved in genome integrity [Resource/Methodology]
Bromodomain proteins (BRD) are key chromatin regulators of genome function and stability as well as therapeutic targets in cancer. Here, we systematically delineate the contribution of human BRD proteins for genome stability and DNA double-strand break (DSB) repair using several cell-based assays and proteomic interaction network analysis. Applying these approaches, we identify 24 of the 42 BRD proteins as promoters of DNA repair and/or genome integrity. We identified a BRD-reader function of PCAF that bound TIP60-mediated histone acetylations at DSBs to recruit a DUB complex to deubiquitylate histone H2BK120, to allowing ...
Source: Genes and Development - December 2, 2019 Category: Genetics & Stem Cells Authors: Kim, J. J., Lee, S. Y., Gong, F., Battenhouse, A. M., Boutz, D. R., Bashyal, A., Refvik, S. T., Chiang, C.-M., Xhemalce, B., Paull, T. T., Brodbelt, J. S., Marcotte, E. M., Miller, K. M. Tags: Resource/Methodology Source Type: research

Paralytic, the Drosophila voltage-gated sodium channel, regulates proliferation of neural progenitors [Research Papers]
Proliferating cells, typically considered "nonexcitable," nevertheless, exhibit regulation by bioelectric signals. Notably, voltage-gated sodium channels (VGSC) that are crucial for neuronal excitability are also found in progenitors and up-regulated in cancer. Here, we identify a role for VGSC in proliferation of Drosophila neuroblast (NB) lineages within the central nervous system. Loss of paralytic (para), the sole gene that encodes Drosophila VGSC, reduces neuroblast progeny cell number. The type II neuroblast lineages, featuring a population of transit-amplifying intermediate neural progenitors (INP) similar...
Source: Genes and Development - December 2, 2019 Category: Genetics & Stem Cells Authors: Piggott, B. J., Peters, C. J., He, Y., Huang, X., Younger, S., Jan, L. Y., Jan, Y. N. Tags: Research Papers Source Type: research

The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis [Research Papers]
More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene RB1. The canonical function of the RB1 gene product, pRB, is to repress the E2F transcription factor family, but pRB also functions to regulate cellular differentiation in part through its binding to the histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A promotes SCLC proliferation and SCLC's neuroendocrine differentiation phenotype in part by sustaining expression of the neuroendocrine transcription factor ASCL1. Mechanistically, we found that KDM5A sustains ASCL1 levels and neuroendoc...
Source: Genes and Development - December 2, 2019 Category: Genetics & Stem Cells Authors: Oser, M. G., Sabet, A. H., Gao, W., Chakraborty, A. A., Schinzel, A. C., Jennings, R. B., Fonseca, R., Bonal, D. M., Booker, M. A., Flaifel, A., Novak, J. S., Christensen, C. L., Zhang, H., Herbert, Z. T., Tolstorukov, M. Y., Buss, E. J., Wong, K.-K., Bro Tags: Research Papers Source Type: research

Crosstalk between Lys63- and Lys11-polyubiquitin signaling at DNA damage sites is driven by Cezanne [Research Papers]
The establishment of polyubiquitin conjugates with distinct linkages play important roles in the DNA damage response. Much remains unknown about the regulation of linkage-specific ubiquitin signaling at sites of DNA damage. Here we reveal that Cezanne (also known as Otud7B) deubiquitinating enzyme promotes the recruitment of Rap80/BRCA1-A complex by binding to Lys63-polyubiquitin and targeting Lys11-polyubiquitin. Using a ubiquitin binding domain protein array screen, we identify that the UBA domains of Cezanne and Cezanne2 (also known as Otud7A) selectively bind to Lys63-linked polyubiquitin. Increased Lys11-linkage ubiqu...
Source: Genes and Development - December 2, 2019 Category: Genetics & Stem Cells Authors: Wu, X., Liu, S., Sagum, C., Chen, J., Singh, R., Chaturvedi, A., Horton, J. R., Kashyap, T. R., Fushman, D., Cheng, X., Bedford, M. T., Wang, B. Tags: Research Papers Source Type: research

Human NORs, comprising rDNA arrays and functionally conserved distal elements, are located within dynamic chromosomal regions [Research Papers]
Human nucleolar organizer regions (NORs), containing ribosomal gene (rDNA) arrays, are located on the p-arms of acrocentric chromosomes (HSA13–15, 21, and 22). Absence of these p-arms from genome references has hampered research on nucleolar formation. Previously, we assembled a distal junction (DJ) DNA sequence contig that abuts rDNA arrays on their telomeric side, revealing that it is shared among the acrocentrics and impacts nucleolar organization. To facilitate inclusion into genome references, we describe sequencing the DJ from all acrocentrics, including three versions of HSA21, ~3 Mb of novel sequence. This wa...
Source: Genes and Development - December 2, 2019 Category: Genetics & Stem Cells Authors: van Sluis, M., Gailin, M. O., McCarter, J. G. W., Mangan, H., Grob, A., McStay, B. Tags: Research Papers Source Type: research

Context-specific regulation of cell survival by a miRNA-controlled BIM rheostat [Research Papers]
Knockout of the ubiquitously expressed miRNA-17~92 cluster in mice produces a lethal developmental lung defect, skeletal abnormalities, and blocked B lymphopoiesis. A shared target of miR-17~92 miRNAs is the pro-apoptotic protein BIM, central to life-death decisions in mammalian cells. To clarify the contribution of miR-17~92:Bim interactions to the complex miR-17~92 knockout phenotype, we used a system of conditional mutagenesis of the nine Bim 3' UTR miR-17~92 seed matches. Blocking miR-17~92:Bim interactions early in development phenocopied the lethal lung phenotype of miR-17~92 ablation and generated a skeletal kinky t...
Source: Genes and Development - December 2, 2019 Category: Genetics & Stem Cells Authors: Labi, V., Peng, S., Klironomos, F., Munschauer, M., Kastelic, N., Chakraborty, T., Schoeler, K., Derudder, E., Martella, M., Mastrobuoni, G., Hernandez-Miranda, L. R., Lahmann, I., Kocks, C., Birchmeier, C., Kempa, S., Quintanilla-Martinez de Fend, L., La Tags: Research Papers Source Type: research

Activation of invariant natural killer T cells stimulates adipose tissue remodeling via adipocyte death and birth in obesity [Research Papers]
In this study, we demonstrate that iNKT cells remove unhealthy adipocytes and stimulate the differentiation of healthy adipocytes. In obese adipose tissue, iNKT cells were abundantly found nearby dead adipocytes. FasL-positive adipose iNKT cells exerted cytotoxic effects to eliminate hypertrophic and pro-inflammatory Fas-positive adipocytes. Furthermore, in vivo adipocyte-lineage tracing mice model showed that activation of iNKT cells by alpha-galactosylceramide promoted adipocyte turnover, eventually leading to potentiation of the insulin-dependent glucose uptake ability in adipose tissue. Collectively, our data propose a...
Source: Genes and Development - December 2, 2019 Category: Genetics & Stem Cells Authors: Park, J., Huh, J. Y., Oh, J., Kim, J. I., Han, S. M., Shin, K. C., Jeon, Y. G., Choe, S. S., Park, J., Kim, J. B. Tags: Research Papers Source Type: research

Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity [Research Papers]
Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein homologous to angiopoietins. Previous studies suggest that tumor cell-derived ANGPTL2 has tumor-promoting function. Here, we conducted mechanistic analysis comparing ANGPTL2 function in cancer progression in a murine syngeneic model of melanoma and a mouse model of translocation renal cell carcinoma (tRCC). ANGPTL2 deficiency in tumor cells slowed tRCC progression, supporting a tumor-promoting role. However, systemic ablation of ANGPTL2 accelerated tRCC progression, supporting a tumor-suppressing role. The syngeneic model also demonstrated a tumor-suppressing...
Source: Genes and Development - December 2, 2019 Category: Genetics & Stem Cells Authors: Horiguchi, H., Kadomatsu, T., Kurahashi, R., Hara, C., Miyata, K., Baba, M., Osumi, H., Terada, K., Araki, K., Takai, T., Kamba, T., Linehan, W. M., Moroishi, T., Oike, Y. Tags: Research Papers Source Type: research

Cell-type-specific dysregulation of RNA alternative splicing in short tandem repeat mouse knockin models of myotonic dystrophy [Research Communications]
Short tandem repeats (STRs) are prone to expansion mutations that cause multiple hereditary neurological and neuromuscular diseases. To study pathomechanisms using mouse models that recapitulate the tissue specificity and developmental timing of an STR expansion gene, we used rolling circle amplification and CRISPR/Cas9-mediated genome editing to generate Dmpk CTG expansion (CTGexp) knockin models of myotonic dystrophy type 1 (DM1). We demonstrate that skeletal muscle myoblasts and brain choroid plexus epithelial cells are particularly susceptible to Dmpk CTGexp mutations and RNA missplicing. Our results implicate dysregul...
Source: Genes and Development - December 2, 2019 Category: Genetics & Stem Cells Authors: Nutter, C. A., Bubenik, J. L., Oliveira, R., Ivankovic, F., Sznajder, Łukasz J., Kidd, B. M., Pinto, B. S., Otero, B. A., Carter, H. A., Vitriol, E. A., Wang, E. T., Swanson, M. S. Tags: Research Communications Source Type: research

Evaluating phase separation in live cells: diagnosis, caveats, and functional consequences [Perspectives]
The idea that liquid–liquid phase separation (LLPS) may be a general mechanism by which molecules in the complex cellular milieu may self-organize has generated much excitement and fervor in the cell biology community. While this concept is not new, its rise to preeminence has resulted in renewed interest in the mechanisms that shape and drive diverse cellular self-assembly processes from gene expression to cell division to stress responses. In vitro biochemical data have been instrumental in deriving some of the fundamental principles and molecular grammar by which biological molecules may phase separate, and the mo...
Source: Genes and Development - December 2, 2019 Category: Genetics & Stem Cells Authors: McSwiggen, D. T., Mir, M., Darzacq, X., Tjian, R. Tags: Methods and Analysis, Chromatin and Gene Expression Perspectives Source Type: research

The human nucleolus organizer regions [Outlook]
Although the nucleolus was first described in the early 19th century from both animal and plant cells, human nucleoli and particularly the five human nucleolus organizers have not been well characterized. In this issue of Genes & Development, van Sluis and colleagues (pp. 1688–1701) present a detailed molecular analysis of these organizers, which occur on the short arms of five human chromosomes. The near identity of these arms suggests extensive interchromosomal exchange during evolutionary history. (Source: Genes and Development)
Source: Genes and Development - December 2, 2019 Category: Genetics & Stem Cells Authors: Gall, J. G. Tags: Chromosome Dynamics and Nuclear Architecture Outlook Source Type: research

Mixed ubiquitin chains regulate DNA repair [Outlook]
Diverse linkage in polyubiquitin chain structure gives cells an unparalleled complexity to virtually modulate all aspects of cell biology. Substrates can be covalently modified by ubiquitin chains of different topology. Proper DNA damage response takes advantage of this regulatory system and heavily relies on ubiquitin-based signaling. Moreover, increasing evidence suggests that chain specificity dictates DNA repair outcome. In this issue of Genes & Development, Wu and colleagues (pp. 1702–1717) show that Cezanne and Cezanne2, two paralogous deubiquitinating enzymes that are recruited to sites of DNA damage, ensu...
Source: Genes and Development - December 2, 2019 Category: Genetics & Stem Cells Authors: Rona, G., Pagano, M. Tags: DNA Recombination and Repair Outlook Source Type: research

Erratum: Dedifferentiation by adenovirus E1A due to inactivation of Hippo pathway effectors YAP and TAZ [Errata]
(Source: Genes and Development)
Source: Genes and Development - November 1, 2019 Category: Genetics & Stem Cells Authors: Zemke, N. R., Gou, D., Berk, A. J. Tags: Errata Source Type: research

Erratum: Single-nucleus transcriptomic survey of cell diversity and functional maturation in postnatal mammalian hearts [Errata]
(Source: Genes and Development)
Source: Genes and Development - November 1, 2019 Category: Genetics & Stem Cells Authors: Hu, P., Liu, J., Zhao, J., Wilkins, B. J., Lupino, K., Wu, H., Pei, L. Tags: Errata Source Type: research

Hi-C guided assemblies reveal conserved regulatory topologies on X and autosomes despite extensive genome shuffling [Resource Methodology]
Genome rearrangements that occur during evolution impose major challenges on regulatory mechanisms that rely on three-dimensional genome architecture. Here, we developed a scaffolding algorithm and generated chromosome-length assemblies from Hi-C data for studying genome topology in three distantly related Drosophila species. We observe extensive genome shuffling between these species with one synteny breakpoint after approximately every six genes. A/B compartments, a set of large gene-dense topologically associating domains (TADs), and spatial contacts between high-affinity sites (HAS) located on the X chromosome are main...
Source: Genes and Development - November 1, 2019 Category: Genetics & Stem Cells Authors: Renschler, G., Richard, G., Valsecchi, C. I. K., Toscano, S., Arrigoni, L., Ramirez, F., Akhtar, A. Tags: Resource Methodology Source Type: research

Planarians recruit piRNAs for mRNA turnover in adult stem cells [Research Papers]
PIWI proteins utilize small RNAs called piRNAs to silence transposable elements, thereby protecting germline integrity. In planarian flatworms, PIWI proteins are essential for regeneration, which requires adult stem cells termed neoblasts. Here, we characterize planarian piRNAs and examine the roles of PIWI proteins in neoblast biology. We find that the planarian PIWI proteins SMEDWI-2 and SMEDWI-3 cooperate to degrade active transposons via the ping-pong cycle. Unexpectedly, we discover that SMEDWI-3 plays an additional role in planarian mRNA surveillance. While SMEDWI-3 degrades numerous neoblast mRNAs in a homotypic pin...
Source: Genes and Development - November 1, 2019 Category: Genetics & Stem Cells Authors: Kim, I. V., Duncan, E. M., Ross, E. J., Gorbovytska, V., Nowotarski, S. H., Elliott, S. A., Sanchez Alvarado, A., Kuhn, C.-D. Tags: Research Papers Source Type: research

Termination of pre-mRNA splicing requires that the ATPase and RNA unwindase Prp43p acts on the catalytic snRNA U6 [Research Papers]
The termination of pre-mRNA splicing functions to discard suboptimal substrates, thereby enhancing fidelity, and to release excised introns in a manner coupled to spliceosome disassembly, thereby allowing recycling. The mechanism of termination, including the RNA target of the DEAH-box ATPase Prp43p, remains ambiguous. We discovered a critical role for nucleotides at the 3' end of the catalytic U6 small nuclear RNA in splicing termination. Although conserved sequence at the 3' end is not required, 2' hydroxyls are, paralleling requirements for Prp43p biochemical activities. Although the 3' end of U6 is not required for rec...
Source: Genes and Development - November 1, 2019 Category: Genetics & Stem Cells Authors: Toroney, R., Nielsen, K. H., Staley, J. P. Tags: Research Papers Source Type: research

Checkpoint inhibition of origin firing prevents DNA topological stress [Research Papers]
A universal feature of DNA damage and replication stress in eukaryotes is the activation of a checkpoint-kinase response. In S-phase, the checkpoint inhibits replication initiation, yet the function of this global block to origin firing remains unknown. To establish the physiological roles of this arm of the checkpoint, we analyzed separation of function mutants in the budding yeast Saccharomyces cerevisiae that allow global origin firing upon replication stress, despite an otherwise normal checkpoint response. Using genetic screens, we show that lack of the checkpoint-block to origin firing results in a dependence on path...
Source: Genes and Development - November 1, 2019 Category: Genetics & Stem Cells Authors: Morafraile, E. C., Hänni, C., Allen, G., Zeisner, T., Clarke, C., Johnson, M. C., Santos, M. M., Carroll, L., Minchell, N. E., Baxter, J., Banks, P., Lydall, D., Zegerman, P. Tags: Research Papers Source Type: research

The Integrator complex cleaves nascent mRNAs to attenuate transcription [Research Papers]
Cellular homeostasis requires transcriptional outputs to be coordinated, and many events post-transcription initiation can dictate the levels and functions of mature transcripts. To systematically identify regulators of inducible gene expression, we performed high-throughput RNAi screening of the Drosophila Metallothionein A (MtnA) promoter. This revealed that the Integrator complex, which has a well-established role in 3' end processing of small nuclear RNAs (snRNAs), attenuates MtnA transcription during copper stress. Integrator complex subunit 11 (IntS11) endonucleolytically cleaves MtnA transcripts, resulting in premat...
Source: Genes and Development - November 1, 2019 Category: Genetics & Stem Cells Authors: Tatomer, D. C., Elrod, N. D., Liang, D., Xiao, M.-S., Jiang, J. Z., Jonathan, M., Huang, K.-L., Wagner, E. J., Cherry, S., Wilusz, J. E. Tags: Research Papers Source Type: research

Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-{beta} signaling [Research Papers]
TGF-β receptors phosphorylate SMAD2 and SMAD3 transcription factors, which then form heterotrimeric complexes with SMAD4 and cooperate with context-specific transcription factors to activate target genes. Here we provide biochemical and structural evidence showing that binding of SMAD2 to DNA depends on the conformation of the E3 insert, a structural element unique to SMAD2 and previously thought to render SMAD2 unable to bind DNA. Based on this finding, we further delineate TGF-β signal transduction by defining distinct roles for SMAD2 and SMAD3 with the forkhead pioneer factor FOXH1 as a partner in the regulati...
Source: Genes and Development - November 1, 2019 Category: Genetics & Stem Cells Authors: Aragon, E., Wang, Q., Zou, Y., Morgani, S. M., Ruiz, L., Kaczmarska, Z., Su, J., Torner, C., Tian, L., Hu, J., Shu, W., Agrawal, S., Gomes, T., Marquez, J. A., Hadjantonakis, A.-K., Macias, M. J., Massague, J. Tags: Research Papers Source Type: research

Hippo pathway deletion in adult resting cardiac fibroblasts initiates a cell state transition with spontaneous and self-sustaining fibrosis [Research Papers]
We report here that Hippo signaling cell-autonomously regulates CF fate transitions and proliferation, and non-cell-autonomously regulates both myeloid and CF activation in the heart. Conditional deletion of Hippo pathway kinases, Lats1 and Lats2, in uninjured CFs initiated a self-perpetuating fibrotic response in the adult heart that was exacerbated by myocardial infarction (MI). Single cell transcriptomics showed that uninjured Lats1/2 mutant CFs spontaneously transitioned to a myofibroblast cell state. Through gene regulatory network reconstruction, we found that Hippo-deficient myofibroblasts deployed a network of tran...
Source: Genes and Development - November 1, 2019 Category: Genetics & Stem Cells Authors: Xiao, Y., Hill, M. C., Li, L., Deshmukh, V., Martin, T. J., Wang, J., Martin, J. F. Tags: Research Papers Source Type: research

Human stem cell models: lessons for pancreatic development and disease [Reviews]
A comprehensive understanding of mechanisms that underlie the development and function of human cells requires human cell models. For the pancreatic lineage, protocols have been developed to differentiate human pluripotent stem cells (hPSCs) into pancreatic endocrine and exocrine cells through intermediates resembling in vivo development. In recent years, this differentiation system has been employed to decipher mechanisms of pancreatic development, congenital defects of the pancreas, as well as genetic forms of diabetes and exocrine diseases. In this review, we summarize recent insights gained from studies of pancreatic h...
Source: Genes and Development - November 1, 2019 Category: Genetics & Stem Cells Authors: Gaertner, B., Carrano, A. C., Sander, M. Tags: Cancer and Disease Models Reviews Source Type: research

Metabolic dependencies and vulnerabilities in leukemia [Reviews]
Leukemia cell proliferation requires up-regulation and rewiring of metabolic pathways to feed anabolic cell growth. Oncogenic drivers directly and indirectly regulate metabolic pathways, and aberrant metabolism is central not only for leukemia proliferation and survival, but also mediates oncogene addiction with significant implications for the development of targeted therapies. This review explores leukemia metabolic circuitries feeding anabolism, redox potential, and energy required for tumor propagation with an emphasis on emerging therapeutic opportunities. (Source: Genes and Development)
Source: Genes and Development - November 1, 2019 Category: Genetics & Stem Cells Authors: Rashkovan, M., Ferrando, A. Tags: Cancer and Disease Models Reviews Source Type: research

Hippo signaling does it again: arbitrating cardiac fibroblast identity and activation [Outlook]
The Hippo pathway is an evolutionarily conserved kinase cascade that is fundamental for tissue development, homeostasis, and regeneration. In the developing mammalian heart, Hippo signaling regulates cardiomyocyte numbers and organ size. While cardiomyocytes in the adult heart are largely postmitotic, Hippo deficiency can increase proliferation of these cells and affect cardiac regenerative capacity. Recent studies have also shown that resident cardiac fibroblasts play a critical role in disease responsiveness and healing, and in this issue of Genes and Development, Xiao and colleagues (pp. 1491–1505) demonstrate tha...
Source: Genes and Development - November 1, 2019 Category: Genetics & Stem Cells Authors: Johansen, A. K. Z., Molkentin, J. D. Tags: Signal Transduction Outlook Source Type: research

An improved auxin-inducible degron system preserves native protein levels and enables rapid and specific protein depletion [Resource/Methodology]
Rapid perturbation of protein function permits the ability to define primary molecular responses while avoiding downstream cumulative effects of protein dysregulation. The auxin-inducible degron (AID) system was developed as a tool to achieve rapid and inducible protein degradation in nonplant systems. However, tagging proteins at their endogenous loci results in chronic auxin-independent degradation by the proteasome. To correct this deficiency, we expressed the auxin response transcription factor (ARF) in an improved inducible degron system. ARF is absent from previously engineered AID systems but is a critical component...
Source: Genes and Development - October 1, 2019 Category: Genetics & Stem Cells Authors: Sathyan, K. M., McKenna, B. D., Anderson, W. D., Duarte, F. M., Core, L., Guertin, M. J. Tags: Resource/Methodology Source Type: research

Automethylation of PRC2 promotes H3K27 methylation and is impaired in H3K27M pediatric glioma [Research Papers]
The histone methyltransferase activity of PRC2 is central to the formation of H3K27me3-decorated facultative heterochromatin and gene silencing. In addition, PRC2 has been shown to automethylate its core subunits, EZH1/EZH2 and SUZ12. Here, we identify the lysine residues at which EZH1/EZH2 are automethylated with EZH2-K510 and EZH2-K514 being the major such sites in vivo. Automethylated EZH2/PRC2 exhibits a higher level of histone methyltransferase activity and is required for attaining proper cellular levels of H3K27me3. While occurring independently of PRC2 recruitment to chromatin, automethylation promotes PRC2 accessi...
Source: Genes and Development - October 1, 2019 Category: Genetics & Stem Cells Authors: Lee, C.-H., Yu, J.-R., Granat, J., Saldana-Meyer, R., Andrade, J., LeRoy, G., Jin, Y., Lund, P., Stafford, J. M., Garcia, B. A., Ueberheide, B., Reinberg, D. Tags: Research Papers Source Type: research

Regulation of histone methylation by automethylation of PRC2 [Research Papers]
Polycomb-repressive complex 2 (PRC2) is a histone methyltransferase that is critical for regulating transcriptional repression in mammals. Its catalytic subunit, EZH2, is responsible for the trimethylation of H3K27 and also undergoes automethylation. Using mass spectrometry analysis of recombinant human PRC2, we identified three methylated lysine residues (K510, K514, and K515) on a disordered but highly conserved loop of EZH2. Methylation of these lysines increases PRC2 histone methyltransferase activity, whereas their mutation decreases activity in vitro. De novo histone methylation in an EZH2 knockout cell line is great...
Source: Genes and Development - October 1, 2019 Category: Genetics & Stem Cells Authors: Wang, X., Long, Y., Paucek, R. D., Gooding, A. R., Lee, T., Burdorf, R. M., Cech, T. R. Tags: Research Papers Source Type: research

Control of homologous recombination by the HROB-MCM8-MCM9 pathway [Research Papers]
DNA repair by homologous recombination (HR) is essential for genomic integrity, tumor suppression, and the formation of gametes. HR uses DNA synthesis to repair lesions such as DNA double-strand breaks and stalled DNA replication forks, but despite having a good understanding of the steps leading to homology search and strand invasion, we know much less of the mechanisms that establish recombination-associated DNA polymerization. Here, we report that C17orf53/HROB is an OB-fold-containing factor involved in HR that acts by recruiting the MCM8–MCM9 helicase to sites of DNA damage to promote DNA synthesis. Mice with ta...
Source: Genes and Development - October 1, 2019 Category: Genetics & Stem Cells Authors: Hustedt, N., Saito, Y., Zimmermann, M., Alvarez-Quilon, A., Setiaputra, D., Adam, S., McEwan, A., Yuan, J. Y., Olivieri, M., Zhao, Y., Kanemaki, M. T., Jurisicova, A., Durocher, D. Tags: Research Papers Source Type: research

ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation [Research Papers]
Short telomere syndromes manifest as familial idiopathic pulmonary fibrosis; they are the most common premature aging disorders. We used genome-wide linkage to identify heterozygous loss of function of ZCCHC8, a zinc-knuckle containing protein, as a cause of autosomal dominant pulmonary fibrosis. ZCCHC8 associated with TR and was required for telomerase function. In ZCCHC8 knockout cells and in mutation carriers, genomically extended telomerase RNA (TR) accumulated at the expense of mature TR, consistent with a role for ZCCHC8 in mediating TR 3' end targeting to the nuclear RNA exosome. We generated Zcchc8-null mice and fo...
Source: Genes and Development - October 1, 2019 Category: Genetics & Stem Cells Authors: Gable, D. L., Gaysinskaya, V., Atik, C. C., Talbot, C. C., Kang, B., Stanley, S. E., Pugh, E. W., Amat-Codina, N., Schenk, K. M., Arcasoy, M. O., Brayton, C., Florea, L., Armanios, M. Tags: Research Papers Source Type: research