Corrigendum: 'Building a perfect body: control of vertebrate organogenesis by PBX-dependent regulatory networks [Corrigendum]
(Source: Genes and Development)
Source: Genes and Development - May 1, 2019 Category: Genetics & Stem Cells Authors: Selleri, L., Zappavigna, V., Ferretti, E. Tags: Corrigendum Source Type: research

In vitro analysis of RNA polymerase II elongation complex dynamics [Research Papers]
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. Chemical inhibition of Kin28/Cdk7 in vitro blocks both Ser5 and Ser2 phosphory...
Source: Genes and Development - May 1, 2019 Category: Genetics & Stem Cells Authors: Joo, Y. J., Ficarro, S. B., Chun, Y., Marto, J. A., Buratowski, S. Tags: Research Papers Source Type: research

Transcriptional gene silencing requires dedicated interaction between HP1 protein Chp2 and chromatin remodeler Mit1 [Research Papers]
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 an...
Source: Genes and Development - May 1, 2019 Category: Genetics & Stem Cells Authors: Leopold, K., Stirpe, A., Schalch, T. Tags: Research Papers Source Type: research

The Set1 complex is dimeric and acts with Jhd2 demethylation to convey symmetrical H3K4 trimethylation [Research Papers]
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 act...
Source: Genes and Development - May 1, 2019 Category: Genetics & Stem Cells Authors: Choudhury, R., Singh, S., Arumugam, S., Roguev, A., Stewart, A. F. Tags: Research Papers Source Type: research

NRDE2 negatively regulates exosome functions by inhibiting MTR4 recruitment and exosome interaction [Research Papers]
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 w...
Source: Genes and Development - May 1, 2019 Category: Genetics & Stem Cells Authors: Wang, J., Chen, J., Wu, G., Zhang, H., Du, X., Chen, S., Zhang, L., Wang, K., Fan, J., Gao, S., Wu, X., Zhang, S., Kuai, B., Zhao, P., Chi, B., Wang, L., Li, G., Wong, C. C. L., Zhou, Y., Li, J., Yun, C., Cheng, H. Tags: Research Papers Source Type: research

Oscillations of MyoD and Hes1 proteins regulate the maintenance of activated muscle stem cells [Research Papers]
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. MyoD expression oscillates in activated muscle stem cells from postnatal and adult muscle under various conditions: w...
Source: Genes and Development - May 1, 2019 Category: Genetics & Stem Cells Authors: Lahmann, I., Bröhl, D., Zyrianova, T., Isomura, A., Czajkowski, M. T., Kapoor, V., Griger, J., Ruffault, P.-L., Mademtzoglou, D., Zammit, P. S., Wunderlich, T., Spuler, S., Kühn, R., Preibisch, S., Wolf, J., Kageyama, R., Birchmeier, C. Tags: Research Papers Source Type: research

High Hes1 expression and resultant Ascl1 suppression regulate quiescent vs. active neural stem cells in the adult mouse brain [Research Papers]
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. Inactivation of Hes1 and its related ...
Source: Genes and Development - May 1, 2019 Category: Genetics & Stem Cells Authors: Sueda, R., Imayoshi, I., Harima, Y., Kageyama, R. Tags: Research Papers Source Type: research

Wnt and Notch signaling govern self-renewal and differentiation in a subset of human glioblastoma stem cells [Research Papers]
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 an...
Source: Genes and Development - May 1, 2019 Category: Genetics & Stem Cells Authors: Rajakulendran, N., Rowland, K. J., Selvadurai, H. J., Ahmadi, M., Park, N. I., Naumenko, S., Dolma, S., Ward, R. J., So, M., Lee, L., MacLeod, G., Pasiliao, C., Brandon, C., Clarke, I. D., Cusimano, M. D., Bernstein, M., Batada, N., Angers, S., Dirks, P. Tags: Research Papers Source Type: research

The splicing factor U2AF1 contributes to cancer progression through a noncanonical role in translation regulation [Research Papers]
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 mR...
Source: Genes and Development - May 1, 2019 Category: Genetics & Stem Cells Authors: Palangat, M., Anastasakis, D. G., Fei, D. L., Lindblad, K. E., Bradley, R., Hourigan, C. S., Hafner, M., Larson, D. R. Tags: Research Papers Source Type: research

HES1, two programs: promoting the quiescence and proliferation of adult neural stem cells [Outlook]
Adult neural stem cells are mostly quiescent and only rarely enter the cell cycle to self-renew and generate neuronal or glial progenies. The Notch signaling pathway is essential for both the quiescent and proliferative states of neural stem cells. However, these are mutually exclusive cellular states; thus, how Notch promotes both of these programs within adult neural stem cells has remained unclear. In this issue of Genes & Development, Sueda and colleagues (pp. 511–523) use an extensive repertoire of mouse genetic tools and techniques to demonstrate that it is the levels and dynamic expression of the Notch tra...
Source: Genes and Development - May 1, 2019 Category: Genetics & Stem Cells Authors: Harris, L., Guillemot, F. Tags: Neurobiology Outlook Source Type: research

Corrigendum: Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome [Corrigendum]
(Source: Genes and Development)
Source: Genes and Development - April 1, 2019 Category: Genetics & Stem Cells Authors: Corradetti, M. N., Inoki, K., Bardeesy, N., DePinho, R. A., Guan, K.-L. Tags: Corrigendum Source Type: research

Auxin regulates endosperm cellularization in Arabidopsis [Research Papers]
The endosperm is an ephemeral tissue that nourishes the developing embryo, similar to the placenta in mammals. In most angiosperms, endosperm development starts as a syncytium, in which nuclear divisions are not followed by cytokinesis. The timing of endosperm cellularization largely varies between species, and the event triggering this transition remains unknown. Here we show that increased auxin biosynthesis in the endosperm prevents its cellularization, leading to seed arrest. Auxin-overproducing seeds phenocopy paternal-excess triploid seeds derived from hybridizations of diploid maternal plants with tetraploid fathers...
Source: Genes and Development - April 1, 2019 Category: Genetics & Stem Cells Authors: Batista, R. A., Figueiredo, D. D., Santos-Gonzalez, J., Köhler, C. Tags: Research Papers Source Type: research

The NSL complex-mediated nucleosome landscape is required to maintain transcription fidelity and suppression of transcription noise [Research Papers]
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. NSL complex member NSL3 binds to TATA-less promoters in a sequence-dependent manner. The NSL comple...
Source: Genes and Development - April 1, 2019 Category: Genetics & Stem Cells Authors: Lam, K. C., Chung, H.-R., Semplicio, G., Iyer, S. S., Gaub, A., Bhardwaj, V., Holz, H., Georgiev, P., Akhtar, A. Tags: Research Papers Source Type: research

Synergistic lethality between BRCA1 and H3K9me2 loss reflects satellite derepression [Research Papers]
Caenorhabditis elegans has two histone H3 Lys9 methyltransferases, MET-2 (SETDB1 homolog) and SET-25 (G9a/SUV39H1 related). In worms, we found simple repeat sequences primarily marked by H3K9me2, while transposable elements and silent tissue-specific genes bear H3K9me3. RNA sequencing (RNA-seq) in histone methyltransferase (HMT) mutants shows that MET-2-mediated H3K9me2 is necessary for satellite repeat repression, while SET-25 silences a subset of transposable elements and tissue-specific genes through H3K9me3. A genome-wide synthetic lethality screen showed that RNA processing, nuclear RNA degradation, the BRCA1/BARD1 co...
Source: Genes and Development - April 1, 2019 Category: Genetics & Stem Cells Authors: Padeken, J., Zeller, P., Towbin, B., Katic, I., Kalck, V., Methot, S. P., Gasser, S. M. Tags: Research Papers Source Type: research

CDK12 phosphorylates 4E-BP1 to enable mTORC1-dependent translation and mitotic genome stability [Research Papers]
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 ta...
Source: Genes and Development - April 1, 2019 Category: Genetics & Stem Cells Authors: Choi, S. H., Martinez, T. F., Kim, S., Donaldson, C., Shokhirev, M. N., Saghatelian, A., Jones, K. A. Tags: Research Papers Source Type: research

Rapid embryonic cell cycles defer the establishment of heterochromatin by Eggless/SetDB1 in Drosophila [Research Papers]
We describe the JabbaTrap, a technique for inactivating maternally provided proteins in embryos. Using the JabbaTrap, we reveal a major requirement for the methyltransferase Eggless/SetDB1 in the establishment of heterochromatin. In contrast, other methyltransferases contribute minimally. Live imaging reveals that endogenous Eggless gradually accumulates on chromatin in interphase but then dissociates in mitosis, and its accumulation must restart in the next cell cycle. Cell cycle slowing as the embryo approaches the MBT permits increasing accumulation and action of Eggless at its targets. Experimental manipulation of inte...
Source: Genes and Development - April 1, 2019 Category: Genetics & Stem Cells Authors: Seller, C. A., Cho, C.-Y., O'Farrell, P. H. Tags: Research Papers Source Type: research

TGIF transcription factors repress acetyl CoA metabolic gene expression and promote intestinal tumor growth [Research Papers]
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....
Source: Genes and Development - April 1, 2019 Category: Genetics & Stem Cells Authors: Shah, A., Melhuish, T. A., Fox, T. E., Frierson, H. F., Wotton, D. Tags: Research Papers Source Type: research

Maternal-biased H3K27me3 correlates with paternal-specific gene expression in the human morula [Research Communications]
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. Thus, our study not only reveals the H3K27me3 landscape but also establishes a correlation between maternal-biased H3K27me3 and PEGs in human morulae. (Source: Genes and Development)
Source: Genes and Development - April 1, 2019 Category: Genetics & Stem Cells Authors: Zhang, W., Chen, Z., Yin, Q., Zhang, D., Racowsky, C., Zhang, Y. Tags: Research Communications Source Type: research

Phasing in heterochromatin during development [Perspectives]
Constitutive heterochromatin is a prevalent feature of eukaryotic genomes important for promoting cell differentiation and maintaining genome stability. During animal reproduction, constitutive heterochromatin is disassembled in gametes prior to formation of the zygote and then subsequently re-established as development ensues and cells differentiate. Despite progress in understanding the mechanisms that maintain heterochromatin in differentiated cell types, how constitutive heterochromatin is assembled de novo during early development remains poorly understood. In this issue of Genes & Development, Seller and colleagu...
Source: Genes and Development - April 1, 2019 Category: Genetics & Stem Cells Authors: Armstrong, R. L., Duronio, R. J. Tags: Methods and Analysis, Chromatin and Gene Expression Perspectives Source Type: research

Corrigendum: Adaptation to DNA damage checkpoint in senescent telomerase-negative cells promotes genome instability [Corrigendum]
(Source: Genes and Development)
Source: Genes and Development - March 1, 2019 Category: Genetics & Stem Cells Authors: Coutelier, H., Xu, Z., Morisse, M. C., Lhuillier-Akakpo, M., Pelet, S., Charvin, G., Dubrana, K., Teixeira, M. T. Tags: Corrigendum Source Type: research

Corrigendum: LMI1 homeodomain protein regulates organ proportions by spatial modulation of endoreduplication [Corrigendum]
(Source: Genes and Development)
Source: Genes and Development - March 1, 2019 Category: Genetics & Stem Cells Authors: Vuolo, F., Kierzkowski, D., Runions, A., Hajheidari, M., Mentink, R. A., Gupta, M. D., Zhang, Z., Vlad, D., Wang, Y., Pecinka, A., Gan, X., Hay, A., Huijser, P., Tsiantis, M. Tags: Corrigendum Source Type: research

Synaptotagmin-11 mediates a vesicle trafficking pathway that is essential for development and synaptic plasticity [Research Papers]
Synaptotagmin-11 (Syt11) is a Synaptotagmin isoform that lacks an apparent ability to bind calcium, phospholipids, or SNARE proteins. While human genetic studies have linked mutations in the Syt11 gene to schizophrenia and Parkinson's disease, the localization or physiological role of Syt11 remain unclear. We found that in neurons, Syt11 resides on abundant vesicles that differ from synaptic vesicles and resemble trafficking endosomes. These vesicles recycle via the plasma membrane in an activity-dependent manner, but their exocytosis is slow and desynchronized. Constitutive knockout mice lacking Syt11 died shortly after b...
Source: Genes and Development - March 1, 2019 Category: Genetics & Stem Cells Authors: Shimojo, M., Madara, J., Pankow, S., Liu, X., Yates, J., Südhof, T. C., Maximov, A. Tags: Research Papers Source Type: research

RNAi-dependent Polycomb repression controls transposable elements in Tetrahymena [Research Papers]
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 s...
Source: Genes and Development - March 1, 2019 Category: Genetics & Stem Cells Authors: Zhao, X., Xiong, J., Mao, F., Sheng, Y., Chen, X., Feng, L., Dui, W., Yang, W., Kapusta, A., Feschotte, C., Coyne, R. S., Miao, W., Gao, S., Liu, Y. Tags: Research Papers Source Type: research

The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms [Research Papers]
SUMOylation (small ubiquitin-like modifier) in the DNA double-strand break (DSB) response regulates recruitment, activity, and clearance of repair factors. However, our understanding of a role for deSUMOylation in this process is limited. Here we identify different mechanistic roles for deSUMOylation in homologous recombination (HR) and nonhomologous end joining (NHEJ) through the investigation of the deSUMOylase SENP2. We found that regulated deSUMOylation of MDC1 prevents excessive SUMOylation and its RNF4-VCP mediated clearance from DSBs, thereby promoting NHEJ. In contrast, we show that HR is differentially sensitive t...
Source: Genes and Development - March 1, 2019 Category: Genetics & Stem Cells Authors: Garvin, A. J., Walker, A. K., Densham, R. M., Chauhan, A. S., Stone, H. R., Mackay, H. L., Jamshad, M., Starowicz, K., Daza-Martin, M., Ronson, G. E., Lanz, A. J., Beesley, J. F., Morris, J. R. Tags: Research Papers Source Type: research

BRN2 suppresses apoptosis, reprograms DNA damage repair, and is associated with a high somatic mutation burden in melanoma [Research Papers]
Whether cell types exposed to a high level of environmental insults possess cell type-specific prosurvival mechanisms or enhanced DNA damage repair capacity is not well understood. BRN2 is a tissue-restricted POU domain transcription factor implicated in neural development and several cancers. In melanoma, BRN2 plays a key role in promoting invasion and regulating proliferation. Here we found, surprisingly, that rather than interacting with transcription cofactors, BRN2 is instead associated with DNA damage response proteins and directly binds PARP1 and Ku70/Ku80. Rapid PARP1-dependent BRN2 association with sites of DNA da...
Source: Genes and Development - March 1, 2019 Category: Genetics & Stem Cells Authors: Herbert, K., Binet, R., Lambert, J.-P., Louphrasitthiphol, P., Kalkavan, H., Sesma-Sanz, L., Robles-Espinoza, C. D., Sarkar, S., Suer, E., Andrews, S., Chauhan, J., Roberts, N. D., Middleton, M. R., Gingras, A.-C., Masson, J.-Y., Larue, L., Falletta, P., Tags: Research Papers Source Type: research

Tissue-specific BMAL1 cistromes reveal that rhythmic transcription is associated with rhythmic enhancer-enhancer interactions [Research Papers]
The mammalian circadian clock relies on the transcription factor CLOCK:BMAL1 to coordinate the rhythmic expression of thousands of genes. Consistent with the various biological functions under clock control, rhythmic gene expression is tissue-specific despite an identical clockwork mechanism in every cell. Here we show that BMAL1 DNA binding is largely tissue-specific, likely because of differences in chromatin accessibility between tissues and cobinding of tissue-specific transcription factors. Our results also indicate that BMAL1 ability to drive tissue-specific rhythmic transcription is associated with not only the acti...
Source: Genes and Development - March 1, 2019 Category: Genetics & Stem Cells Authors: Beytebiere, J. R., Trott, A. J., Greenwell, B. J., Osborne, C. A., Vitet, H., Spence, J., Yoo, S.-H., Chen, Z., Takahashi, J. S., Ghaffari, N., Menet, J. S. Tags: Research Papers Source Type: research

Sfp1 regulates transcriptional networks driving cell growth and division through multiple promoter-binding modes [Research Communications]
The yeast Sfp1 protein regulates both cell division and growth but how it coordinates these processes is poorly understood. We demonstrate that Sfp1 directly controls genes required for ribosome production and many other growth-promoting processes. Remarkably, the complete set of Sfp1 target genes is revealed only by a combination of ChIP (chromatin immunoprecipitation) and ChEC (chromatin endogenous cleavage) methods, which uncover two promoter binding modes, one requiring a cofactor and the other a DNA-recognition motif. Glucose-regulated Sfp1 binding at cell cycle "START" genes suggests that Sfp1 controls cell...
Source: Genes and Development - March 1, 2019 Category: Genetics & Stem Cells Authors: Albert, B., Tomassetti, S., Gloor, Y., Dilg, D., Mattarocci, S., Kubik, S., Hafner, L., Shore, D. Tags: Research Communications Source Type: research

DNA polymerase {theta} accomplishes translesion synthesis opposite 1,N6-ethenodeoxyadenosine with a remarkably high fidelity in human cells [Research Communications]
Here we show that translesion synthesis (TLS) opposite 1,N6-ethenodeoxyadenosine (dA), which disrupts Watson–Crick base pairing, occurs via Pol/Pol-, Rev1-, and Pol-dependent pathways. The requirement of Pol/Pol is consistent with the ability of Pol to incorporate nucleotide opposite dA by Hoogsteen base pairing and of Pol to extend synthesis. Rev1 polymerase and Pol conduct TLS opposite dA via alternative error-prone pathways. Strikingly, in contrast to extremely error-prone TLS opposite dA by purified Pol, it performs predominantly error-free TLS in human cells. Reconfiguration of the active site opposite dA would ...
Source: Genes and Development - March 1, 2019 Category: Genetics & Stem Cells Authors: Yoon, J.-H., Johnson, R. E., Prakash, L., Prakash, S. Tags: Research Communications Source Type: research

Resolution of human ribosomal DNA occurs in anaphase, dependent on tankyrase 1, condensin II, and topoisomerase II{alpha} [Research Communications]
Formation of individualized sister chromatids is essential for their accurate segregation. In budding yeast, while most of the genome segregates at the metaphase to anaphase transition, resolution of the ribosomal DNA (rDNA) repeats is delayed. The timing and mechanism in human cells is unknown. Here we show that resolution of human rDNA occurs in anaphase after the bulk of the genome, dependent on tankyrase 1, condensin II, and topoisomerase IIα. Defective resolution leads to rDNA bridges, rDNA damage, and aneuploidy of an rDNA-containing acrocentric chromosome. Thus, temporal regulation of rDNA segregation is conse...
Source: Genes and Development - March 1, 2019 Category: Genetics & Stem Cells Authors: Daniloski, Z., Bisht, K. K., McStay, B., Smith, S. Tags: Research Communications Source Type: research

'Building a perfect body: control of vertebrate organogenesis by PBX-dependent regulatory networks [Reviews]
Pbx genes encode transcription factors that belong to the TALE (three-amino-acid loop extension) superclass of homeodomain proteins. We have witnessed a surge in information about the roles of this gene family as leading actors in the transcriptional control of development. PBX proteins represent a clear example of how transcription factors can regulate developmental processes by combinatorial properties, acting within multimeric complexes to implement activation or repression of transcription depending on their interaction partners. Here, we revisit long-emphasized functions of PBX transcription factors as cofactors for H...
Source: Genes and Development - March 1, 2019 Category: Genetics & Stem Cells Authors: Selleri, L., Zappavigna, V., Ferretti, E. Tags: Development, Cell Biology, Chromatin and Gene Expression Reviews Source Type: research

Help from my friends--cooperation of BMAL1 with noncircadian transcription factors [Outlook]
The circadian clock in the suprachiasmatic nucleus (SCN) of mammals drives 24-h rhythms of sleep/wake cycles. Peripheral clocks present in other organs coordinate local and global physiology according to rhythmic signals from the SCN and via metabolic cues. The core circadian clockwork is identical in all cells. However, there is only a small amount of overlap of the circadian transcriptomes in different organs and tissues. A novel study by Beytebiere and colleagues (pp. 294–309) indicates that the regulation of tissue-specific rhythmic gene expression involves the cooperation of the circadian transcription factor (T...
Source: Genes and Development - March 1, 2019 Category: Genetics & Stem Cells Authors: Shostak, A., Brunner, M. Tags: Molecular Physiology and Metabolism, Chromosome Dynamics and Nuclear Architecture Outlook Source Type: research

Erratum: Localized protein biotinylation at DNA damage sites identifies ZPET, a repressor of homologous recombination [Errata]
(Source: Genes and Development)
Source: Genes and Development - February 1, 2019 Category: Genetics & Stem Cells Authors: Moquin, D. M., Genois, M.-M., Zhang, J.-M., Ouyang, J., Yadav, T., Buisson, R., Yazinski, S. A., Tan, J., Boukhali, M., Gagne, J.-P., Poirier, G. G., Lan, L., Haas, W., Zou, L. Tags: Errata Source Type: research

A conserved CAF40-binding motif in metazoan NOT4 mediates association with the CCR4-NOT complex [Research Papers]
The multisubunit CCR4–NOT mRNA deadenylase complex plays important roles in the posttranscriptional regulation of gene expression. The NOT4 E3 ubiquitin ligase is a stable component of the CCR4–NOT complex in yeast but does not copurify with the human or Drosophila melanogaster complex. Here we show that the C-terminal regions of human and D. melanogaster NOT4 contain a conserved sequence motif that directly binds the CAF40 subunit of the CCR4–NOT complex (CAF40-binding motif [CBM]). In addition, nonconserved sequences flanking the CBM also contact other subunits of the complex. Crystal structures of the ...
Source: Genes and Development - February 1, 2019 Category: Genetics & Stem Cells Authors: Keskeny, C., Raisch, T., Sgromo, A., Igreja, C., Bhandari, D., Weichenrieder, O., Izaurralde, E. Tags: Research Papers Source Type: research

RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening [Research Papers]
Approximately 15% of cancers use homologous recombination for alternative lengthening of telomeres (ALT). How the initiating genomic lesions invoke homology-directed telomere synthesis remains enigmatic. Here, we show that distinct dependencies exist for telomere synthesis in response to replication stress or DNA double-strand breaks (DSBs). RAD52 deficiency reduced spontaneous telomeric DNA synthesis and replication stress-associated recombination in G2, concomitant with telomere shortening and damage. However, viability and proliferation remained unaffected, suggesting that alternative telomere recombination mechanisms c...
Source: Genes and Development - February 1, 2019 Category: Genetics & Stem Cells Authors: Verma, P., Dilley, R. L., Zhang, T., Gyparaki, M. T., Li, Y., Greenberg, R. A. Tags: Research Papers Source Type: research

A ZNRF3-dependent Wnt/{beta}-catenin signaling gradient is required for adrenal homeostasis [Research Papers]
Spatiotemporal control of Wnt signaling is essential for the development and homeostasis of many tissues. The transmembrane E3 ubiquitin ligases ZNRF3 (zinc and ring finger 3) and RNF43 (ring finger protein 43) antagonize Wnt signaling by promoting degradation of frizzled receptors. ZNRF3 and RNF43 are frequently inactivated in human cancer, but the molecular and therapeutic implications remain unclear. Here, we demonstrate that adrenocortical-specific loss of ZNRF3, but not RNF43, results in adrenal hyperplasia that depends on Porcupine-mediated Wnt ligand secretion. Furthermore, we discovered a Wnt/β-catenin signali...
Source: Genes and Development - February 1, 2019 Category: Genetics & Stem Cells Authors: Basham, K. J., Rodriguez, S., Turcu, A. F., Lerario, A. M., Logan, C. Y., Rysztak, M. R., Gomez-Sanchez, C. E., Breault, D. T., Koo, B.-K., Clevers, H., Nusse, R., Val, P., Hammer, G. D. Tags: Research Papers Source Type: research

Dppa2 and Dppa4 directly regulate the Dux-driven zygotic transcriptional program [Research Papers]
The molecular regulation of zygotic genome activation (ZGA) in mammals remains an exciting area of research. Primed mouse embryonic stem cells contain a rare subset of "2C-like" cells that are epigenetically and transcriptionally similar to the two-cell embryo and thus represent an in vitro approximation for studying ZGA transcription regulation. Recently, the transcription factor Dux, expressed in the minor wave of ZGA, was described to activate many downstream ZGA transcripts. However, it remains unknown what upstream maternal factors initiate ZGA in either a Dux-dependent or Dux-independent manner. Here we per...
Source: Genes and Development - February 1, 2019 Category: Genetics & Stem Cells Authors: Eckersley-Maslin, M., Alda-Catalinas, C., Blotenburg, M., Kreibich, E., Krueger, C., Reik, W. Tags: Research Papers Source Type: research

Afadin cooperates with Claudin-2 to promote breast cancer metastasis [Research Papers]
Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that the PDZ-binding motif of Claudin-2 is necessary for anchorage-independent growth of cancer cells and is required for liver metastasis. Several PDZ domain-containing proteins were identified that interact with the PDZ-binding motif of Claudin-2 in liver metastatic breast cancer cells, including Afadin, Arhgap21, Pdlim2, Pdlim7, Rims2, Scrib, and ZO-1. We specifically examined the role of Afadin as a potential Claudin-2-interacting partner that promotes breast cancer liver metastasis. Afadin associate...
Source: Genes and Development - February 1, 2019 Category: Genetics & Stem Cells Authors: Tabaries, S., McNulty, A., Ouellet, V., Annis, M. G., Dessureault, M., Vinette, M., Hachem, Y., Lavoie, B., Omeroglu, A., Simon, H.-G., Walsh, L. A., Kimbung, S., Hedenfalk, I., Siegel, P. M. Tags: Research Papers Source Type: research

CD44 splice isoform switching determines breast cancer stem cell state [Research Papers]
Although changes in alternative splicing have been observed in cancer, their functional contributions still remain largely unclear. Here we report that splice isoforms of the cancer stem cell (CSC) marker CD44 exhibit strikingly opposite functions in breast cancer. Bioinformatic annotation in patient breast cancer in The Cancer Genome Atlas (TCGA) database reveals that the CD44 standard splice isoform (CD44s) positively associates with the CSC gene signatures, whereas the CD44 variant splice isoforms (CD44v) exhibit an inverse association. We show that CD44s is the predominant isoform expressed in breast CSCs. Elimination ...
Source: Genes and Development - February 1, 2019 Category: Genetics & Stem Cells Authors: Zhang, H., Brown, R. L., Wei, Y., Zhao, P., Liu, S., Liu, X., Deng, Y., Hu, X., Zhang, J., Gao, X. D., Kang, Y., Mercurio, A. M., Goel, H. L., Cheng, C. Tags: Research Papers Source Type: research

Autophagy modulates lipid metabolism to maintain metabolic flexibility for Lkb1-deficient Kras-driven lung tumorigenesis [Research Papers]
Loss of tumor suppressor liver kinase B1 (LKB1) promotes cancer cell proliferation but also leads to decreased metabolic plasticity in dealing with energy crises. Autophagy is a protective process involving self-cannibalization to maintain cellular energy homeostasis during nutrient deprivation. We developed a mouse model for Lkb1-deficient lung cancer with conditional deletion of essential autophagy gene Atg7 to test whether autophagy compensates for LKB1 loss for tumor cells to survive energy crises. We found that autophagy ablation was synthetically lethal during Lkb1-deficient lung tumorigenesis in both tumor initiatio...
Source: Genes and Development - February 1, 2019 Category: Genetics & Stem Cells Authors: Bhatt, V., Khayati, K., Hu, Z. S., Lee, A., Kamran, W., Su, X., Guo, J. Y. Tags: Research Papers Source Type: research

Nuclear pore density controls heterochromatin reorganization during senescence [Research Communications]
During oncogene-induced senescence (OIS), heterochromatin is lost from the nuclear periphery and forms internal senescence-associated heterochromatin foci (SAHFs). We show that an increased nuclear pore density during OIS is responsible for SAHF formation. In particular, the nucleoporin TPR is necessary for both formation and maintenance of SAHFs. Loss of SAHFs does not affect cell cycle arrest but abrogates the senescence-associated secretory phenotype—a program of inflammatory cytokine gene activation. Our results uncover a previously unknown role of nuclear pores in heterochromatin reorganization in mammalian nucl...
Source: Genes and Development - February 1, 2019 Category: Genetics & Stem Cells Authors: Boumendil, C., Hari, P., Olsen, K. C. F., Acosta, J. C., Bickmore, W. A. Tags: Research Communications Source Type: research

Short-term gain, long-term pain: the senescence life cycle and cancer [Reviews]
Originally thought of as a stress response end point, the view of cellular senescence has since evolved into one encompassing a wide range of physiological and pathological functions, including both protumorignic and antitumorigenic features. It has also become evident that senescence is a highly dynamic and heterogenous process. Efforts to reconcile the beneficial and detrimental features of senescence suggest that physiological functions require the transient presence of senescent cells in the tissue microenvironment. Here, we propose the concept of a physiological "senescence life cycle," which has pathologica...
Source: Genes and Development - February 1, 2019 Category: Genetics & Stem Cells Authors: Chan, A. S. L., Narita, M. Tags: Cell Biology, Cell Cycle and DNA Replication, Cancer and Disease Models Reviews Source Type: research

Anti-silencing factor Epe1 associates with SAGA to regulate transcription within heterochromatin [Research Papers]
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. By screening the fission yeast deletion library, we found that...
Source: Genes and Development - January 2, 2019 Category: Genetics & Stem Cells Authors: Bao, K., Shan, C.-M., Moresco, J., Yates, J., Jia, S. Tags: Research Papers Source Type: research

Timely double-strand break repair and pathway choice in pericentromeric heterochromatin depend on the histone demethylase dKDM4A [Research Papers]
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. Here we used locus-specific DSB induction in Drosophila animal ...
Source: Genes and Development - January 2, 2019 Category: Genetics & Stem Cells Authors: Janssen, A., Colmenares, S. U., Lee, T., Karpen, G. H. Tags: Research Papers Source Type: research

The USTC co-opts an ancient machinery to drive piRNA transcription in C. elegans [Research Papers]
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. The USTC co...
Source: Genes and Development - January 2, 2019 Category: Genetics & Stem Cells Authors: Weng, C., Kosalka, J., Berkyurek, A. C., Stempor, P., Feng, X., Mao, H., Zeng, C., Li, W.-J., Yan, Y.-H., Dong, M.-Q., Morero, N. R., Zuliani, C., Barabas, O., Ahringer, J., Guang, S., Miska, E. A. Tags: Research Papers Source Type: research

Localized protein biotinylation at DNA damage sites identifies ZPET, a repressor of homologous recombination [Research Papers]
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. In cells, ZPET delays MRE11 binding to chromatin after DSB formation and slows DNA end resection through bindin...
Source: Genes and Development - January 2, 2019 Category: Genetics & Stem Cells Authors: Moquin, D. M., Genois, M.-M., Zhang, J.-M., Ouyang, J., Yadav, T., Buisson, R., Yazinski, S. A., Tan, J., Boukhali, M., Gagne, J.-P., Poirier, G. G., Lan, L., Haas, W., Zou, L. Tags: Research Papers Source Type: research

Regulation of MLL/COMPASS stability through its proteolytic cleavage by taspase1 as a possible approach for clinical therapy of leukemia [Research Papers]
This study provides insights into the direct regulation of the stability of MLL1 through its cleavage by taspase1, which can be harnessed for targeted therapeutic approaches for the treatment of aggressive leukemia as the result of MLL translocations. (Source: Genes and Development)
Source: Genes and Development - January 2, 2019 Category: Genetics & Stem Cells Authors: Zhao, Z., Wang, L., Volk, A. G., Birch, N. W., Stoltz, K. L., Bartom, E. T., Marshall, S. A., Rendleman, E. J., Nestler, C. M., Shilati, J., Schiltz, G. E., Crispino, J. D., Shilatifard, A. Tags: Research Papers Source Type: research

PRC1 preserves epidermal tissue integrity independently of PRC2 [Research Communications]
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. In contrast, PRC1 promotes expression of critical epidermal adhesion gen...
Source: Genes and Development - January 2, 2019 Category: Genetics & Stem Cells Authors: Cohen, I., Zhao, D., Menon, G., Nakayama, M., Koseki, H., Zheng, D., Ezhkova, E. Tags: Research Communications Source Type: research

ZNF445 is a primary regulator of genomic imprinting [Research Communications]
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 ZNF4...
Source: Genes and Development - January 2, 2019 Category: Genetics & Stem Cells Authors: Takahashi, N., Coluccio, A., Thorball, C. W., Planet, E., Shi, H., Offner, S., Turelli, P., Imbeault, M., Ferguson-Smith, A. C., Trono, D. Tags: Research Communications Source Type: research

Molecular regulation of peripheral B cells and their progeny in immunity [Reviews]
Mature B lymphocytes are crucial components of adaptive immunity, a system essential for the evolutionary fitness of mammals. Adaptive lymphocyte function requires an initially naìˆve 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. An overview is combined with an account of more recent...
Source: Genes and Development - January 2, 2019 Category: Genetics & Stem Cells Authors: Boothby, M. R., Hodges, E., Thomas, J. W. Tags: Cell Biology, Immunology Reviews Source Type: research

Helix-loop-helix proteins and the advent of cellular diversity: 30 years of discovery [Reviews]
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. HLH proteins also regulate circadian clocks, protect ...
Source: Genes and Development - January 2, 2019 Category: Genetics & Stem Cells Authors: Murre, C. Tags: Reviews Source Type: research