Break-induced replication promotes fragile telomere formation [Research Papers]
We report that analogous to CFSs, fragile telomeres in BLM-deficient cells involved double-strand break (DSB) formation, in this case by the SLX4/SLX1 nuclease. The DSBs were repaired by POLD3/POLD4-dependent break-induced replication (BIR), resulting in fragile telomeres containing conservatively replicated DNA. BIR also promoted fragile telomere formation in cells with FokI-induced telomeric DSBs and in alternative lengthening of telomeres (ALT) cells, which have spontaneous telomeric damage. BIR of telomeric DSBs competed with PARP1-, LIG3-, and XPF-dependent alternative nonhomologous end joining (alt-NHEJ), which did n...
Source: Genes and Development - October 1, 2020 Category: Genetics & Stem Cells Authors: Yang, Z., Takai, K. K., Lovejoy, C. A., de Lange, T. Tags: Research Papers Source Type: research

Context-dependent functional compensation between Ythdf m6A reader proteins [Research Papers]
The N6-methyladenosine (m6A) modification is the most prevalent post-transcriptional mRNA modification, regulating mRNA decay and splicing. It plays a major role during normal development, differentiation, and disease progression. The modification is regulated by a set of writer, eraser, and reader proteins. The YTH domain family of proteins consists of three homologous m6A-binding proteins, Ythdf1, Ythdf2, and Ythdf3, which were suggested to have different cellular functions. However, their sequence similarity and their tendency to bind the same targets suggest that they may have overlapping roles. We systematically knock...
Source: Genes and Development - October 1, 2020 Category: Genetics & Stem Cells Authors: Lasman, L., Krupalnik, V., Viukov, S., Mor, N., Aguilera-Castrejon, A., Schneir, D., Bayerl, J., Mizrahi, O., Peles, S., Tawil, S., Sathe, S., Nachshon, A., Shani, T., Zerbib, M., Kilimnik, I., Aigner, S., Shankar, A., Mueller, J. R., Schwartz, S., Stern- Tags: Research Papers Source Type: research

ASB13 inhibits breast cancer metastasis through promoting SNAI2 degradation and relieving its transcriptional repression of YAP [Research Papers]
Transcription factor SNAI2 plays key roles during development and has also been known to promote metastasis by inducing invasive phenotype and tumor-initiating activity of cancer cells. However, the post-translational regulation of SNAI2 is less well studied. We performed a dual-luciferase-based, genome-wide E3 ligase siRNA library screen and identified ASB13 as an E3 ubiquitin ligase that targets SNAI2 for ubiquitination and degradation. ASB13 knockout in breast cancer cells promoted cell migration and decreased F-actin polymerization, while overexpression of ASB13 suppressed lung metastasis. Furthermore, ASB13 knockout d...
Source: Genes and Development - October 1, 2020 Category: Genetics & Stem Cells Authors: Fan, H., Wang, X., Li, W., Shen, M., Wei, Y., Zheng, H., Kang, Y. Tags: Research Papers Source Type: research

Yap/Taz promote the scavenging of extracellular nutrients through macropinocytosis [Research Papers]
The uptake of macromolecules and cellular debris through macropinocytosis has emerged as an important nutrient acquisition strategy of cancer cells. Genetic alterations commonly found in human cancers (e.g. mutations in KRAS or loss of PTEN) have been shown to increase macropinocytosis. To identify additional effectors that enable cell growth dependent on the uptake of extracellular proteins, pancreatic ductal adenocarcinoma (PDA) cells were selected for growth in medium where extracellular albumin was the obligate source of the essential amino acid leucine. Analysis of global changes in chromatin availability and gene exp...
Source: Genes and Development - October 1, 2020 Category: Genetics & Stem Cells Authors: King, B., Araki, J., Palm, W., Thompson, C. B. Tags: Research Papers Source Type: research

AMPK regulation of Raptor and TSC2 mediate metformin effects on transcriptional control of anabolism and inflammation [Research Papers]
Despite being the frontline therapy for type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB, but several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1. Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new RaptorAA mouse model, in which AMPK phospho-serine sites Se...
Source: Genes and Development - October 1, 2020 Category: Genetics & Stem Cells Authors: Van Nostrand, J. L., Hellberg, K., Luo, E.-C., Van Nostrand, E. L., Dayn, A., Yu, J., Shokhirev, M. N., Dayn, Y., Yeo, G. W., Shaw, R. J. Tags: Research Papers Source Type: research

SMARCB1 loss interacts with neuronal differentiation state to block maturation and impact cell stability [Research Papers]
Atypical teratoid rhabdoid tumors (ATRTs) are challenging pediatric brain cancers that are predominantly associated with inactivation of the gene SMARCB1, a conserved subunit of the chromatin remodeling BAF complex, which has known contributions to developmental processes. To identify potential interactions between SMARCB1 loss and the process of neural development, we introduced an inducible SMARCB1 loss-of-function system into human induced pluripotent stem cells (iPSCs) that were subjected to either directed neuronal differentiation or differentiation into cerebral organoids. Using this system, we identified substantial...
Source: Genes and Development - October 1, 2020 Category: Genetics & Stem Cells Authors: Parisian, A. D., Koga, T., Miki, S., Johann, P. D., Kool, M., Crawford, J. R., Furnari, F. B. Tags: Research Papers Source Type: research

Deubiquitinase USP20 promotes breast cancer metastasis by stabilizing SNAI2 [Research Communications]
SNAI2/SLUG, a metastasis-promoting transcription factor, is a labile protein that is degraded through the ubiquitin proteasome degradation system. Here, we conducted comprehensive gain- and loss-of-function screens using a human DUB cDNA library of 65 genes and an siRNA library of 98 genes, and identified USP20 as a deubiquitinase (DUB) that regulates SNAI2 ubiquitination and stability. Further investigation of USP20 demonstrated its function in promoting migration, invasion, and metastasis of breast cancer. USP20 positively correlates with SNAI2 protein level in breast tumor samples, and higher USP20 expression is associa...
Source: Genes and Development - October 1, 2020 Category: Genetics & Stem Cells Authors: Li, W., Shen, M., Jiang, Y.-Z., Zhang, R., Zheng, H., Wei, Y., Shao, Z.-M., Kang, Y. Tags: Research Communications Source Type: research

Point-activated ESR1Y541S has a dramatic effect on the development of sexually dimorphic organs [Research Communications]
Mutations in the estrogen receptor α (ERα) occur in endocrine-resistant metastatic breast cancer. However, a major gap persists with the lack of genetically tractable immune competent mouse models to study disease. Hence, we developed a Cre-inducible murine model expressing a point-activated ESR1Y541S (ESR1Y537S in humans) driven by its endogenous promoter. Germline expression of mutant ESR1Y541S reveals dramatic developmental defects in the reproductive organs, mammary glands, and bones of the mice. These observations provide critical insights into the tissue-specific roles of ERα during development and ...
Source: Genes and Development - October 1, 2020 Category: Genetics & Stem Cells Authors: Simond, A. M., Ling, C., Moore, M. J., Condotta, S. A., Richer, M. J., Muller, W. J. Tags: Research Communications Source Type: research

The SAGA chromatin-modifying complex: the sum of its parts is greater than the whole [Reviews]
There are many large protein complexes involved in transcription in a chromatin context. However, recent studies on the SAGA coactivator complex are generating new paradigms for how the components of these complexes function, both independently and in concert. This review highlights the initial discovery of the canonical SAGA complex 23 years ago, our evolving understanding of its modular structure and the relevance of its modular nature for its coactivator function in gene regulation. (Source: Genes and Development)
Source: Genes and Development - October 1, 2020 Category: Genetics & Stem Cells Authors: Soffers, J. H. M., Workman, J. L. Tags: Chromatin and Gene Expression Reviews Source Type: research

A most formidable arsenal: genetic technologies for building a better mouse [Reviews]
The mouse is one of the most widely used model organisms for genetic study. The tools available to alter the mouse genome have developed over the preceding decades from forward screens to gene targeting in stem cells to the recent influx of CRISPR approaches. In this review, we first consider the history of mice in genetic study, the development of classic approaches to genome modification, and how such approaches have been used and improved in recent years. We then turn to the recent surge of nuclease-mediated techniques and how they are changing the field of mouse genetics. Finally, we survey common classes of alleles us...
Source: Genes and Development - October 1, 2020 Category: Genetics & Stem Cells Authors: Clark, J. F., Dinsmore, C. J., Soriano, P. Tags: Cancer and Disease Models Reviews Source Type: research

Transcriptional activation of macropinocytosis by the Hippo pathway following nutrient limitation [Outlook]
Cancer cells must adapt metabolism to thrive despite nutrient limitations in the tumor microenvironment. In this issue of Genes & Development, King and colleagues (pp. 1345–1358) report a role for transcriptional regulators of the Hippo pathway to facilitate protein scavenging and support proliferation under some nutrient-deprived conditions. (Source: Genes and Development)
Source: Genes and Development - October 1, 2020 Category: Genetics & Stem Cells Authors: Sivanand, S., Vander Heiden, M. G. Tags: Chromatin and Gene Expression Outlook Source Type: research

Distinct kinesin motors drive two types of maize neocentromeres [Research Papers]
A maize chromosome variant called abnormal chromosome 10 (Ab10) converts knobs on chromosome arms into neocentromeres, causing their preferential segregation to egg cells in a process known as meiotic drive. We previously demonstrated that the gene Kinesin driver (Kindr) on Ab10 encodes a kinesin-14 required to mobilize neocentromeres made up of the major tandem repeat knob180. Here we describe a second kinesin-14 gene, TR-1 kinesin (Trkin), that is required to mobilize neocentromeres made up of the minor tandem repeat TR-1. Trkin lies in a 4-Mb region of Ab10 that is not syntenic with any other region of the maize genome ...
Source: Genes and Development - September 1, 2020 Category: Genetics & Stem Cells Authors: Swentowsky, K. W., Gent, J. I., Lowry, E. G., Schubert, V., Ran, X., Tseng, K.-F., Harkess, A. E., Qiu, W., Dawe, R. K. Tags: Research Papers Source Type: research

In vivo CRISPR screening for phenotypic targets of the mir-35-42 family in C. elegans [Research Papers]
This study demonstrates that the application of in vivo whole organismal CRISPR screening has great potential to accelerate the discovery of phenotypic negative regulatory elements in the noncoding genome. (Source: Genes and Development)
Source: Genes and Development - September 1, 2020 Category: Genetics & Stem Cells Authors: Yang, B., Schwartz, M., McJunkin, K. Tags: Research Papers Source Type: research

MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity [Research Papers]
Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by initial chemosensitivity followed by emergence of chemoresistant disease. To study roles for MYCN amplification in SCLC progression and chemoresistance, we developed a genetically engineered mouse model of MYCN-overexpressing SCLC. In treatment-naìˆve mice, MYCN overexpression promoted cell cycle progression, suppressed infiltration of cytotoxic T cells, and accelerated SCLC. MYCN overexpression also suppressed response to cisplatin–etoposide chemotherapy, with similar findings made upon MYCL overexpression. We extended these data ...
Source: Genes and Development - September 1, 2020 Category: Genetics & Stem Cells Authors: Grunblatt, E., Wu, N., Zhang, H., Liu, X., Norton, J. P., Ohol, Y., Leger, P., Hiatt, J. B., Eastwood, E. C., Thomas, R., Ibrahim, A. H., Jia, D., Basom, R., Eaton, K. D., Martins, R., Houghton, A. M., MacPherson, D. Tags: Research Papers Source Type: research

Phf21b imprints the spatiotemporal epigenetic switch essential for neural stem cell differentiation [Research Papers]
Cerebral cortical development in mammals involves a highly complex and organized set of events including the transition of neural stem and progenitor cells (NSCs) from proliferative to differentiative divisions to generate neurons. Despite progress, the spatiotemporal regulation of this proliferation-differentiation switch during neurogenesis and the upstream epigenetic triggers remain poorly known. Here we report a cortex-specific PHD finger protein, Phf21b, which is highly expressed in the neurogenic phase of cortical development and gets induced as NSCs begin to differentiate. Depletion of Phf21b in vivo inhibited neuro...
Source: Genes and Development - September 1, 2020 Category: Genetics & Stem Cells Authors: Basu, A., Mestres, I., Sahu, S. K., Tiwari, N., Khongwir, B., Baumgart, J., Singh, A., Calegari, F., Tiwari, V. K. Tags: Research Papers Source Type: research

The Daam2-VHL-Nedd4 axis governs developmental and regenerative oligodendrocyte differentiation [Research Papers]
Dysregulation of the ubiquitin–proteasomal system (UPS) enables pathogenic accumulation of disease-driving proteins in neurons across a host of neurological disorders. However, whether and how the UPS contributes to oligodendrocyte dysfunction and repair after white matter injury (WMI) remains undefined. Here we show that the E3 ligase VHL interacts with Daam2 and their mutual antagonism regulates oligodendrocyte differentiation during development. Using proteomic analysis of the Daam2–VHL complex coupled with conditional genetic knockout mouse models, we further discovered that the E3 ubiquitin ligase Nedd4 is...
Source: Genes and Development - September 1, 2020 Category: Genetics & Stem Cells Authors: Ding, X., Jo, J., Wang, C.-Y., Cristobal, C. D., Zuo, Z., Ye, Q., Wirianto, M., Lindeke-Myers, A., Choi, J. M., Mohila, C. A., Kawabe, H., Jung, S. Y., Bellen, H. J., Yoo, S.-H., Lee, H. K. Tags: Research Papers Source Type: research

Functional loss of a noncanonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation [Research Papers]
Medulloblastoma is a malignant childhood brain tumor arising from the developing cerebellum. In Sonic Hedgehog (SHH) subgroup medulloblastoma, aberrant activation of SHH signaling causes increased proliferation of granule neuron progenitors (GNPs), and predisposes these cells to tumorigenesis. A second, cooperating genetic hit is often required to push these hyperplastic cells to malignancy and confer mutation-specific characteristics associated with oncogenic signaling. Somatic loss-of-function mutations of the transcriptional corepressor BCOR are recurrent and enriched in SHH medulloblastoma. To investigate BCOR as a put...
Source: Genes and Development - September 1, 2020 Category: Genetics & Stem Cells Authors: Kutscher, L. M., Okonechnikov, K., Batora, N. V., Clark, J., Silva, P. B. G., Vouri, M., van Rijn, S., Sieber, L., Statz, B., Gearhart, M. D., Shiraishi, R., Mack, N., Orr, B. A., Korshunov, A., Gudenas, B. L., Smith, K. S., Mercier, A. L., Ayrault, O., H Tags: Research Papers Source Type: research

miR760 regulates ATXN1 levels via interaction with its 5' untranslated region [Research Papers]
In this study, we focus on Ataxin-1 (ATXN1), a dosage-sensitive gene involved in the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1). While the precise maintenance of ATXN1 levels is essential to prevent disease, the mechanisms that regulate ATXN1 expression remain largely unknown. We demonstrate that ATXN1’s unusually long 5' untranslated region (5' UTR) negatively regulates its expression via posttranscriptional mechanisms. Based on recent reports that microRNAs (miRNAs) can interact with both 3' and 5' UTRs to regulate their target genes, we identify miR760 as a negative regulator that binds to a co...
Source: Genes and Development - September 1, 2020 Category: Genetics & Stem Cells Authors: Nitschke, L., Tewari, A., Coffin, S. L., Xhako, E., Pang, K., Gennarino, V. A., Johnson, J. L., Blanco, F. A., Liu, Z., Zoghbi, H. Y. Tags: Research Papers Source Type: research

p53 tetramerization: at the center of the dominant-negative effect of mutant p53 [Reviews]
The p53 tumor suppressor functions as a tetrameric transcription factor to regulate hundreds of genes—many in a tissue-specific manner. Missense mutations in cancers in the p53 DNA-binding and tetramerization domains cement the importance of these domains in tumor suppression. p53 mutants with a functional tetramerization domain form mixed tetramers, which in some cases have dominant-negative effects (DNE) that inactivate wild-type p53. DNA damage appears necessary but not sufficient for DNE, indicating that upstream signals impact DNE. Posttranslational modifications and protein–protein interactions alter p53 ...
Source: Genes and Development - September 1, 2020 Category: Genetics & Stem Cells Authors: Gencel-Augusto, J., Lozano, G. Tags: Cancer and Disease Models Reviews Source Type: research

The nuclear cap-binding complex as choreographer of gene transcription and pre-mRNA processing [Reviews]
We describe parameters known to control the binding of generic or gene-specific cofactors that regulate CBC activities depending on the process(es) targeted, illustrating how the CBC is an ever-changing choreographer of gene expression. (Source: Genes and Development)
Source: Genes and Development - September 1, 2020 Category: Genetics & Stem Cells Authors: Rambout, X., Maquat, L. E. Tags: Chromatin and Gene Expression Reviews Source Type: research

Mixed knobs in corn cobs [Outlook]
Maize heterochromatic knobs cheat female meiosis by forming neocentromeres that bias their segregation into the future egg cell. In this issue of Genes & Development, Swentowsky and colleagues (pp. 1239–1251) show that two types of knobs, those composed of 180-bp and TR1 sequences, recruit their own novel and divergent kinesin-14 family members to form neocentromeres. (Source: Genes and Development)
Source: Genes and Development - September 1, 2020 Category: Genetics & Stem Cells Authors: Lamelza, P., Lampson, M. A. Tags: Outlook Source Type: research

UTteR control through miRs: fine-tuning ATXN1 levels to prevent ataxia [Outlook]
Pathomechanistic studies of neurodegenerative diseases have documented the toxic effects of mutant protein expression, misfolding, and aggregation. However, alterations in the expression of the corresponding wild-type (WT) gene, due to either variations in copy number or transcriptional regulation, have also been linked to Alzheimer's and Parkinson's diseases. Another striking example of this mutant and WT duality is spinocerebellar ataxia type 1 (SCA1) caused by an ATXN1 polyglutamine protein, although subtle variations in WT AXTN1 levels also lead to ataxia. In this issue of Genes & Development, Nitschke and colleagu...
Source: Genes and Development - September 1, 2020 Category: Genetics & Stem Cells Authors: Xie, M., Swanson, M. S. Tags: Post-transcriptional Control, Neurobiology Outlook Source Type: research

Erratum: Set1/COMPASS repels heterochromatin invasion at euchromatic sites by disrupting Suv39/Clr4 activity and nucleosome stability [Errata]
(Source: Genes and Development)
Source: Genes and Development - August 3, 2020 Category: Genetics & Stem Cells Authors: Greenstein, R. A., Barrales, R. R., Sanchez, N. A., Bisanz, J. E., Braun, S., Al-Sady, B. Tags: Errata Source Type: research

A role for alternative splicing in circadian control of exocytosis and glucose homeostasis [Research Papers]
The circadian clock is encoded by a negative transcriptional feedback loop that coordinates physiology and behavior through molecular programs that remain incompletely understood. Here, we reveal rhythmic genome-wide alternative splicing (AS) of pre-mRNAs encoding regulators of peptidergic secretion within pancreatic β cells that are perturbed in Clock–/– and Bmal1–/– β-cell lines. We show that the RNA-binding protein THRAP3 (thyroid hormone receptor-associated protein 3) regulates circadian clock-dependent AS by binding to exons at coding sequences flanking exons that are more frequently ...
Source: Genes and Development - August 3, 2020 Category: Genetics & Stem Cells Authors: Marcheva, B., Perelis, M., Weidemann, B. J., Taguchi, A., Lin, H., Omura, C., Kobayashi, Y., Newman, M. V., Wyatt, E. J., McNally, E. M., Fox, J. E. M., Hong, H., Shankar, A., Wheeler, E. C., Ramsey, K. M., MacDonald, P. E., Yeo, G. W., Bass, J. Tags: Research Papers Source Type: research

Identification of a localized nonsense-mediated decay pathway at the endoplasmic reticulum [Research Papers]
Nonsense-mediated decay (NMD) is a translation-dependent RNA quality control mechanism that occurs in the cytoplasm. However, it is unknown how NMD regulates the stability of RNAs translated at the endoplasmic reticulum (ER). Here, we identify a localized NMD pathway dedicated to ER-translated mRNAs. We previously identified NBAS, a component of the Syntaxin 18 complex involved in Golgi-to-ER trafficking, as a novel NMD factor. Furthermore, we show that NBAS fulfills an independent function in NMD. This ER–NMD pathway requires the interaction of NBAS with the core NMD factor UPF1, which is partially localized at the ...
Source: Genes and Development - August 3, 2020 Category: Genetics & Stem Cells Authors: Longman, D., Jackson-Jones, K. A., Maslon, M. M., Murphy, L. C., Young, R. S., Stoddart, J. J., Hug, N., Taylor, M. S., Papadopoulos, D. K., Caceres, J. F. Tags: Research Papers Source Type: research

Human RTEL1 associates with Poldip3 to facilitate responses to replication stress and R-loop resolution [Research Papers]
RTEL1 helicase is a component of DNA repair and telomere maintenance machineries. While RTEL1's role in DNA replication is emerging, how RTEL1 preserves genomic stability during replication remains elusive. Here we used a range of proteomic, biochemical, cell, and molecular biology and gene editing approaches to provide further insights into potential role(s) of RTEL1 in DNA replication and genome integrity maintenance. Our results from complementary human cell culture models established that RTEL1 and the Pol subunit Poldip3 form a complex and are/function mutually dependent in chromatin binding after replication stress. ...
Source: Genes and Development - August 3, 2020 Category: Genetics & Stem Cells Authors: Björkman, A., Johansen, S. L., Lin, L., Schertzer, M., Kanellis, D. C., Katsori, A.-M., Christensen, S. T., Luo, Y., Andersen, J. S., Elsässer, S. J., Londono-Vallejo, A., Bartek, J., Schou, K. B. Tags: Research Papers Source Type: research

Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis [Research Papers]
YAP1 is a transcriptional coactivator and the principal effector of the Hippo signaling pathway, which is causally implicated in human cancer. Several YAP1 gene fusions have been identified in various human cancers and identifying the essential components of this family of gene fusions has significant therapeutic value. Here, we show that the YAP1 gene fusions YAP1-MAMLD1, YAP1-FAM118B, YAP1-TFE3, and YAP1-SS18 are oncogenic in mice. Using reporter assays, RNA-seq, ChIP-seq, and loss-of-function mutations, we can show that all of these YAP1 fusion proteins exert TEAD-dependent YAP activity, while some also exert activity o...
Source: Genes and Development - August 3, 2020 Category: Genetics & Stem Cells Authors: Szulzewsky, F., Arora, S., Hoellerbauer, P., King, C., Nathan, E., Chan, M., Cimino, P. J., Ozawa, T., Kawauchi, D., Pajtler, K. W., Gilbertson, R. J., Paddison, P. J., Vasioukhin, V., Gujral, T. S., Holland, E. C. Tags: Research Papers Source Type: research

Collapse of the hepatic gene regulatory network in the absence of FoxA factors [Research Papers]
The FoxA transcription factors are critical for liver development through their pioneering activity, which initiates a highly complex regulatory network thought to become progressively resistant to the loss of any individual hepatic transcription factor via mutual redundancy. To investigate the dispensability of FoxA factors for maintaining this regulatory network, we ablated all FoxA genes in the adult mouse liver. Remarkably, loss of FoxA caused rapid and massive reduction in the expression of critical liver genes. Activity of these genes was reduced back to the low levels of the fetal prehepatic endoderm stage, leading ...
Source: Genes and Development - August 3, 2020 Category: Genetics & Stem Cells Authors: Reizel, Y., Morgan, A., Gao, L., Lan, Y., Manduchi, E., Waite, E. L., Wang, A. W., Wells, A., Kaestner, K. H. Tags: Research Papers Source Type: research

Neural production of kynurenic acid in Caenorhabditis elegans requires the AAT-1 transporter [Research Communications]
Kynurenic acid (KynA) levels link peripheral metabolic status to neural functions including learning and memory. Since neural KynA levels dampen learning capacity, KynA reduction has been proposed as a therapeutic strategy for conditions of cognitive deficit such as neurodegeneration. While KynA is generated locally within the nervous system, its precursor, kynurenine (Kyn), is largely derived from peripheral resources. The mechanisms that import Kyn into the nervous system are poorly understood. Here, we provide genetic, anatomical, biochemical, and behavioral evidence showing that in C. elegans an ortholog of the human L...
Source: Genes and Development - August 3, 2020 Category: Genetics & Stem Cells Authors: Lin, L., Lemieux, G. A., Enogieru, O. J., Giacomini, K. M., Ashrafi, K. Tags: Research Communications Source Type: research

Cells of origin of lung cancers: lessons from mouse studies [Reviews]
As one of the most common forms of cancer, lung cancers present as a collection of different histological subtypes. These subtypes are characterized by distinct sets of driver mutations and phenotypic appearance, and they often show varying degrees of heterogenicity, aggressiveness, and response/resistance to therapy. Intriguingly, lung cancers are also capable of showing features of multiple subtypes or converting from one subtype to another. The intertumoral and intratumoral heterogeneity of lung cancers as well as incidences of subtype transdifferentiation raise the question of to what extent the tumor characteristics a...
Source: Genes and Development - August 3, 2020 Category: Genetics & Stem Cells Authors: Ferone, G., Lee, M. C., Sage, J., Berns, A. Tags: Cancer and Disease Models Reviews Source Type: research

Alternative splicing and cancer: insights, opportunities, and challenges from an expanding view of the transcriptome [Reviews]
Over the past decade there has been increased awareness of the potential role of alternative splicing in the etiology of cancer. In particular, advances in RNA-Sequencing technology and analysis has led to a wave of discoveries in the last few years regarding the causes and functional relevance of alternative splicing in cancer. Here we discuss the current understanding of the connections between splicing and cancer, with a focus on the most recent findings. We also discuss remaining questions and challenges that must be addressed in order to use our knowledge of splicing to guide the diagnosis and treatment of cancer. (So...
Source: Genes and Development - August 3, 2020 Category: Genetics & Stem Cells Authors: Cherry, S., Lynch, K. W. Tags: Chromatin and Gene Expression, Cancer and Disease Models Reviews Source Type: research

FoxA factors: the chromatin key and doorstop essential for liver development and function [Outlook]
Pioneer factors are transcriptional regulators with the capacity to bind inactive regions of chromatin and induce changes in accessibility that underpin cell fate decisions. The FOXA family of transcription factors is well understood to have pioneer capacity. Indeed, researchers have uncovered numerous examples of FOXA-dependent epigenomic modulation in developmental and disease processes. Despite the presence of FOXA being essential for correct epigenetic patterning, the need for continued FOXA presence postchromatin modulation has been debated. In a recent study in this issue of Genes & Development, Reizel and collea...
Source: Genes and Development - August 3, 2020 Category: Genetics & Stem Cells Authors: Heslop, J. A., Duncan, S. A. Tags: Chromatin and Gene Expression Outlook Source Type: research

Competition between maturation and degradation drives human snRNA 3' end quality control [Research Papers]
Polymerases and exonucleases act on 3' ends of nascent RNAs to promote their maturation or degradation but how the balance between these activities is controlled to dictate the fates of cellular RNAs remains poorly understood. Here, we identify a central role for the human DEDD deadenylase TOE1 in distinguishing the fates of small nuclear (sn)RNAs of the spliceosome from unstable genome-encoded snRNA variants. We found that TOE1 promotes maturation of all regular RNA polymerase II transcribed snRNAs of the major and minor spliceosomes by removing posttranscriptional oligo(A) tails, trimming 3' ends, and preventing nuclear ...
Source: Genes and Development - July 1, 2020 Category: Genetics & Stem Cells Authors: Lardelli, R. M., Lykke-Andersen, J. Tags: Research Papers Source Type: research

HDAC3 ensures stepwise epidermal stratification via NCoR/SMRT-reliant mechanisms independent of its histone deacetylase activity [Research Papers]
Chromatin modifiers play critical roles in epidermal development, but the functions of histone deacetylases in this context are poorly understood. The class I HDAC, HDAC3, is of particular interest because it plays divergent roles in different tissues by partnering with tissue-specific transcription factors. We found that HDAC3 is expressed broadly in embryonic epidermis and is required for its orderly stepwise stratification. HDAC3 protein stability in vivo relies on NCoR and SMRT, which function redundantly in epidermal development. However, point mutations in the NCoR and SMRT deacetylase-activating domains, which are r...
Source: Genes and Development - July 1, 2020 Category: Genetics & Stem Cells Authors: Szigety, K. M., Liu, F., Yuan, C. Y., Moran, D. J., Horrell, J., Gochnauer, H. R., Cohen, R. N., Katz, J. P., Kaestner, K. H., Seykora, J. T., Tobias, J. W., Lazar, M. A., Xu, M., Millar, S. E. Tags: Research Papers Source Type: research

Twist-dependent ratchet functioning downstream from Dorsal revealed using a light-inducible degron [Research Papers]
This study demonstrates that continuous input is not required for some Dorsal targets and downstream responses, such as twist, function as molecular ratchets. (Source: Genes and Development)
Source: Genes and Development - July 1, 2020 Category: Genetics & Stem Cells Authors: Irizarry, J., McGehee, J., Kim, G., Stein, D., Stathopoulos, A. Tags: Research Papers Source Type: research

Transcriptional regulatory network controlling the ontogeny of hematopoietic stem cells [Research Papers]
Hematopoietic stem cell (HSC) ontogeny is accompanied by dynamic changes in gene regulatory networks. We performed RNA-seq and histone mark ChIP-seq to define the transcriptomes and epigenomes of cells representing key developmental stages of HSC ontogeny in mice. The five populations analyzed were embryonic day 10.5 (E10.5) endothelium and hemogenic endothelium from the major arteries, an enriched population of prehematopoietic stem cells (pre-HSCs), fetal liver HSCs, and adult bone marrow HSCs. Using epigenetic signatures, we identified enhancers for each developmental stage. Only 12% of enhancers are primed, and 78% are...
Source: Genes and Development - July 1, 2020 Category: Genetics & Stem Cells Authors: Gao, P., Chen, C., Howell, E. D., Li, Y., Tober, J., Uzun, Y., He, B., Gao, L., Zhu, Q., Siekmann, A. F., Speck, N. A., Tan, K. Tags: Research Papers Source Type: research

A central role for canonical PRC1 in shaping the 3D nuclear landscape [Research Papers]
Polycomb group (PcG) proteins silence gene expression by chemically and physically modifying chromatin. A subset of PcG target loci are compacted and cluster in the nucleus; a conformation that is thought to contribute to gene silencing. However, how these interactions influence gross nuclear organization and their relationship with transcription remains poorly understood. Here we examine the role of Polycomb-repressive complex 1 (PRC1) in shaping 3D genome organization in mouse embryonic stem cells (mESCs). Using a combination of imaging and Hi-C analyses, we show that PRC1-mediated long-range interactions are independent...
Source: Genes and Development - July 1, 2020 Category: Genetics & Stem Cells Authors: Boyle, S., Flyamer, I. M., Williamson, I., Sengupta, D., Bickmore, W. A., Illingworth, R. S. Tags: Research Papers Source Type: research

Dynamic regulation of histone modifications and long-range chromosomal interactions during postmitotic transcriptional reactivation [Research Papers]
During mitosis, transcription of genomic DNA is dramatically reduced, before it is reactivated during nuclear reformation in anaphase/telophase. Many aspects of the underlying principles that mediate transcriptional memory and reactivation in the daughter cells remain unclear. Here, we used ChIP-seq on synchronized cells at different stages after mitosis to generate genome-wide maps of histone modifications. Combined with EU-RNA-seq and Hi-C analyses, we found that during prometaphase, promoters, enhancers, and insulators retain H3K4me3 and H3K4me1, while losing H3K27ac. Enhancers globally retaining mitotic H3K4me1 or loca...
Source: Genes and Development - July 1, 2020 Category: Genetics & Stem Cells Authors: Kang, H., Shokhirev, M. N., Xu, Z., Chandran, S., Dixon, J. R., Hetzer, M. W. Tags: Research Papers Source Type: research

UAP56/DDX39B is a major cotranscriptional RNA-DNA helicase that unwinds harmful R loops genome-wide [Research Papers]
Nonscheduled R loops represent a major source of DNA damage and replication stress. Cells have different ways to prevent R-loop accumulation. One mechanism relies on the conserved THO complex in association with cotranscriptional RNA processing factors including the RNA-dependent ATPase UAP56/DDX39B and histone modifiers such as the SIN3 deacetylase in humans. We investigated the function of UAP56/DDX39B in R-loop removal. We show that UAP56 depletion causes R-loop accumulation, R-loop-mediated genome instability, and replication fork stalling. We demonstrate an RNA–DNA helicase activity in UAP56 and show that its ov...
Source: Genes and Development - July 1, 2020 Category: Genetics & Stem Cells Authors: Perez-Calero, C., Bayona-Feliu, A., Xue, X., Barroso, S. I., Munoz, S., Gonzalez-Basallote, V. M., Sung, P., Aguilera, A. Tags: Research Papers Source Type: research

Nutrient-dependent control of RNA polymerase II elongation rate regulates specific gene expression programs by alternative polyadenylation [Research Papers]
Transcription by RNA polymerase II (RNAPII) is a dynamic process with frequent variations in the elongation rate. However, the physiological relevance of variations in RNAPII elongation kinetics has remained unclear. Here we show in yeast that a RNAPII mutant that reduces the transcription elongation rate causes widespread changes in alternative polyadenylation (APA). We unveil two mechanisms by which APA affects gene expression in the slow mutant: 3' UTR shortening and gene derepression by premature transcription termination of upstream interfering noncoding RNAs. Strikingly, the genes affected by these mechanisms are enr...
Source: Genes and Development - July 1, 2020 Category: Genetics & Stem Cells Authors: Yague-Sanz, C., Vanrobaeys, Y., Fernandez, R., Duval, M., Larochelle, M., Beaudoin, J., Berro, J., Labbe, S., Jacques, P.-E., Bachand, F. Tags: Research Papers Source Type: research

RNA polymerase III transcription as a disease factor [Reviews]
RNA polymerase (Pol) III is responsible for transcription of different noncoding genes in eukaryotic cells, whose RNA products have well-defined functions in translation and other biological processes for some, and functions that remain to be defined for others. For all of them, however, new functions are being described. For example, Pol III products have been reported to regulate certain proteins such as protein kinase R (PKR) by direct association, to constitute the source of very short RNAs with regulatory roles in gene expression, or to control microRNA levels by sequestration. Consistent with these many functions, de...
Source: Genes and Development - July 1, 2020 Category: Genetics & Stem Cells Authors: Yeganeh, M., Hernandez, N. Tags: Chromatin and Gene Expression Reviews Source Type: research

A genome-wide and cotranscriptional suppressor of R loops [Outlook]
R loops arise from hybridization of RNA transcripts with template DNA during transcription. Unrepaired R loops lead to transcription–replication collisions, causing DNA damage and genomic instability. In this issue of Genes & Development, Pérez-Calero and colleagues (pp. 898–912) identify UAP56 as a cotranscriptional RNA–DNA helicase that unwinds R loops. They found that UAP56 helicase activity is required to remove R loops formed from different sources and prevent R-loop accumulation genome-wide at actively transcribed genes. (Source: Genes and Development)
Source: Genes and Development - July 1, 2020 Category: Genetics & Stem Cells Authors: Matson, J. P., Zou, L. Tags: DNA Recombination and Repair Outlook Source Type: research

Corrigendum: Developmental regulation of cell type-specific transcription by novel promoter-proximal sequence elements [Errata]
(Source: Genes and Development)
Source: Genes and Development - June 1, 2020 Category: Genetics & Stem Cells Authors: Lu, D., Sin, H.-S., Lu, C., Fuller, M. T. Tags: Errata Source Type: research

4E-T-bound mRNAs are stored in a silenced and deadenylated form [Research Papers]
Human 4E-T is an eIF4E-binding protein (4E-BP) present in processing (P)-bodies that represses translation and regulates decay of mRNAs destabilized by AU-rich elements and microRNAs (miRNAs). However, the underlying regulatory mechanisms are still unclear. Here, we show that upon mRNA binding 4E-T represses translation and promotes deadenylation via the recruitment of the CCR4–NOT deadenylase complex. The interaction with CCR4–NOT is mediated by previously uncharacterized sites in the middle region of 4E-T. Importantly, mRNA decapping and decay are inhibited by 4E-T and the deadenylated target is stored in a r...
Source: Genes and Development - June 1, 2020 Category: Genetics & Stem Cells Authors: Räsch, F., Weber, R., Izaurralde, E., Igreja, C. Tags: Research Papers Source Type: research

Distinct roles of BRCA2 in replication fork protection in response to hydroxyurea and DNA interstrand cross-links [Research Papers]
DNA interstrand cross-links (ICLs) are a form of DNA damage that requires the interplay of a number of repair proteins including those of the Fanconi anemia (FA) and the homologous recombination (HR) pathways. Pathogenic variants in the essential gene BRCA2/FANCD1, when monoallelic, predispose to breast and ovarian cancer, and when biallelic, result in a severe subtype of Fanconi anemia. BRCA2 function in the FA pathway is attributed to its role as a mediator of the RAD51 recombinase in HR repair of programmed DNA double-strand breaks (DSB). BRCA2 and RAD51 functions are also required to protect stalled replication forks f...
Source: Genes and Development - June 1, 2020 Category: Genetics & Stem Cells Authors: Rickman, K. A., Noonan, R. J., Lach, F. P., Sridhar, S., Wang, A. T., Abhyankar, A., Huang, A., Kelly, M., Auerbach, A. D., Smogorzewska, A. Tags: Research Papers Source Type: research

The spatial regulation of condensin activity in chromosome condensation [Research Papers]
Condensin mediates chromosome condensation, which is essential for proper chromosome segregation during mitosis. Prior to anaphase of budding yeast, the ribosomal DNA (RDN) condenses to a thin loop that is distinct from the rest of the chromosomes. We provide evidence that the establishment and maintenance of this RDN condensation requires the regulation of condensin by Cdc5p (polo) kinase. We show that Cdc5p is recruited to the site of condensin binding in the RDN by cohesin, a complex related to condensin. Cdc5p and cohesin prevent condensin from misfolding the RDN into an irreversibly decondensed state. From these and o...
Source: Genes and Development - June 1, 2020 Category: Genetics & Stem Cells Authors: Lamothe, R., Costantino, L., Koshland, D. E. Tags: Research Papers Source Type: research

Molecular structures and mechanisms of DNA break processing in mouse meiosis [Research Papers]
Exonucleolytic resection, critical to repair double-strand breaks (DSBs) by recombination, is not well understood, particularly in mammalian meiosis. Here, we define structures of resected DSBs in mouse spermatocytes genome-wide at nucleotide resolution. Resection tracts averaged 1100 nt, but with substantial fine-scale heterogeneity at individual hot spots. Surprisingly, EXO1 is not the major 5' -> 3' exonuclease, but the DSB-responsive kinase ATM proved a key regulator of both initiation and extension of resection. In wild type, apparent intermolecular recombination intermediates clustered near to but offset from DSB ...
Source: Genes and Development - June 1, 2020 Category: Genetics & Stem Cells Authors: Yamada, S., Hinch, A. G., Kamido, H., Zhang, Y., Edelmann, W., Keeney, S. Tags: Research Papers Source Type: research

ALS/FTD-associated protein FUS induces mitochondrial dysfunction by preferentially sequestering respiratory chain complex mRNAs [Research Papers]
Dysregulation of the DNA/RNA-binding protein FUS causes certain subtypes of ALS/FTD by largely unknown mechanisms. Recent evidence has shown that FUS toxic gain of function due either to mutations or to increased expression can disrupt critical cellular processes, including mitochondrial functions. Here, we demonstrate that in human cells overexpressing wild-type FUS or expressing mutant derivatives, the protein associates with multiple mRNAs, and these are enriched in mRNAs encoding mitochondrial respiratory chain components. Notably, this sequestration leads to reduced levels of the encoded proteins, which is sufficient ...
Source: Genes and Development - June 1, 2020 Category: Genetics & Stem Cells Authors: Tsai, Y.-L., Coady, T. H., Lu, L., Zheng, D., Alland, I., Tian, B., Shneider, N. A., Manley, J. L. Tags: Research Papers Source Type: research

Transcriptional down-regulation of metabolic genes by Gdown1 ablation induces quiescent cell re-entry into the cell cycle [Research Papers]
Liver regeneration and metabolism are highly interconnected. Here, we show that hepatocyte-specific ablation of RNA polymerase II (Pol II)-associated Gdown1 leads to down-regulation of highly expressed genes involved in plasma protein synthesis and metabolism, a concomitant cell cycle re-entry associated with induction of cell cycle-related genes (including cyclin D1), and up-regulation of p21 through activation of p53 signaling. In the absence of p53, Gdown1-deficient hepatocytes show a severe dysregulation of cell cycle progression, with incomplete mitoses, and a premalignant-like transformation. Mechanistically, Gdown1 ...
Source: Genes and Development - June 1, 2020 Category: Genetics & Stem Cells Authors: Jishage, M., Ito, K., Chu, C.-S., Wang, X., Yamaji, M., Roeder, R. G. Tags: Research Papers Source Type: research

REDD1 loss reprograms lipid metabolism to drive progression of RAS mutant tumors [Research Papers]
Human cancers with activating RAS mutations are typically highly aggressive and treatment-refractory, yet RAS mutation itself is insufficient for tumorigenesis, due in part to profound metabolic stress induced by RAS activation. Here we show that loss of REDD1, a stress-induced metabolic regulator, is sufficient to reprogram lipid metabolism and drive progression of RAS mutant cancers. Redd1 deletion in genetically engineered mouse models (GEMMs) of KRAS-dependent pancreatic and lung adenocarcinomas converts preneoplastic lesions into invasive and metastatic carcinomas. Metabolic profiling reveals that REDD1-deficient/RAS ...
Source: Genes and Development - June 1, 2020 Category: Genetics & Stem Cells Authors: Qiao, S., Koh, S.-B., Vivekanandan, V., Salunke, D., Patra, K. C., Zaganjor, E., Ross, K., Mizukami, Y., Jeanfavre, S., Chen, A., Mino-Kenudson, M., Ramaswamy, S., Clish, C., Haigis, M., Bardeesy, N., Ellisen, L. W. Tags: Research Papers Source Type: research