The biological underpinnings of therapeutic resistance in pancreatic cancer [Reviews]
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the United States and has only recently achieved a 5-yr survival rate of 10%. This dismal prognosis reflects the remarkable capacity of PDAC to effectively adapt to and resist therapeutic intervention. In this review, we discuss recent advances in our understanding of the biological underpinnings of PDAC and their implications as targetable vulnerabilities in this highly lethal disease. (Source: Genes and Development)
Source: Genes and Development - July 1, 2021 Category: Genetics & Stem Cells Authors: Beatty, G. L., Werba, G., Lyssiotis, C. A., Simeone, D. M. Tags: Cancer and Disease Models Reviews Source Type: research
Kinesin-1 captures RNA cargo in its adaptable coils [Outlook]
The prototypic and ubiquitous microtubule motor, kinesin-1, uses a variety of adaptor proteins to facilitate the selective transport of diverse cargo within the cell. These cargo adaptors bind to the motor complex through interactions with the kinesin light or heavy chains (KLCs or KHCs). In this issue of Genes & Development, Dimitrova-Paternoga et al. (pp. 976–991) present the first structural characterization of a KHC–cargo adaptor interface. They describe an antiparallel heterotrimeric coiled-coil complex between the carboxy tail of KHC and Tm1-I/C (aTm1), the atypical tropomyosin that is important for o...
Source: Genes and Development - July 1, 2021 Category: Genetics & Stem Cells Authors: Cross, J. A., Woolfson, D. N., Dodding, M. P. Tags: Structural Biology Outlook Source Type: research
piRNA-mediated gene regulation and adaptation to sex-specific transposon expression in D. melanogaster male germline [Research Papers]
Small noncoding piRNAs act as sequence-specific guides to repress complementary targets in Metazoa. Prior studies in Drosophila ovaries have demonstrated the function of the piRNA pathway in transposon silencing and therefore genome defense. However, the ability of the piRNA program to respond to different transposon landscapes and the role of piRNAs in regulating host gene expression remain poorly understood. Here, we comprehensively analyzed piRNA expression and defined the repertoire of their targets in Drosophila melanogaster testes. Comparison of piRNA programs between sexes revealed sexual dimorphism in piRNA program...
Source: Genes and Development - June 1, 2021 Category: Genetics & Stem Cells Authors: Chen, P., Kotov, A. A., Godneeva, B. K., Bazylev, S. S., Olenina, L. V., Aravin, A. A. Tags: Research Papers Source Type: research
Natural antisense transcript of Period2, Per2AS, regulates the amplitude of the mouse circadian clock [Research Papers]
In mammals, a set of core clock genes form transcription–translation feedback loops to generate circadian oscillations. We and others recently identified a novel transcript at the Period2 (Per2) locus that is transcribed from the antisense strand of Per2. This transcript, Per2AS, is expressed rhythmically and antiphasic to Per2 mRNA, leading to our hypothesis that Per2AS and Per2 mutually inhibit each other's expression and form a double negative feedback loop. By perturbing the expression of Per2AS, we found that Per2AS transcription, but not transcript, represses Per2. However, Per2 does not repress Per2AS, as Per2...
Source: Genes and Development - June 1, 2021 Category: Genetics & Stem Cells Authors: Mosig, R. A., Castaneda, A. N., Deslauriers, J. C., Frazier, L. P., He, K. L., Maghzian, N., Pokharel, A., Schrier, C. T., Zhu, L., Koike, N., Tyson, J. J., Green, C. B., Takahashi, J. S., Kojima, S. Tags: Research Papers Source Type: research
Natural temperature fluctuations promote COOLAIR regulation of FLC [Research Papers]
Plants monitor many aspects of their fluctuating environments to help align their development with seasons. Molecular understanding of how noisy temperature cues are registered has emerged from dissection of vernalization in Arabidopsis, which involves a multiphase cold-dependent silencing of the floral repressor locus FLOWERING LOCUS C (FLC). Cold-induced transcriptional silencing precedes a low probability PRC2 epigenetic switching mechanism. The epigenetic switch requires the absence of warm temperatures as well as long-term cold exposure. However, the natural temperature inputs into the earlier transcriptional silencin...
Source: Genes and Development - June 1, 2021 Category: Genetics & Stem Cells Authors: Zhao, Y., Zhu, P., Hepworth, J., Bloomer, R., Antoniou-Kourounioti, R. L., Doughty, J., Heckmann, A., Xu, C., Yang, H., Dean, C. Tags: Research Papers Source Type: research
Protein neddylation as a therapeutic target in pulmonary and extrapulmonary small cell carcinomas [Research Papers]
Small cell lung carcinoma (SCLC) is among the most lethal of all solid tumor malignancies. In an effort to identify novel therapeutic approaches for this recalcitrant cancer type, we applied genome-scale CRISPR/Cas9 inactivation screens to cell lines that we derived from a murine model of SCLC. SCLC cells were particularly sensitive to the deletion of NEDD8 and other neddylation pathway genes. Genetic suppression or pharmacological inhibition of this pathway using MLN4924 caused cell death not only in mouse SCLC cell lines but also in patient-derived xenograft (PDX) models of pulmonary and extrapulmonary small cell carcino...
Source: Genes and Development - June 1, 2021 Category: Genetics & Stem Cells Authors: Norton, J. P., Augert, A., Eastwood, E., Basom, R., Rudin, C. M., MacPherson, D. Tags: Research Papers Source Type: research
ASCL1 represses a SOX9+ neural crest stem-like state in small cell lung cancer [Research Papers]
ASCL1 is a neuroendocrine lineage-specific oncogenic driver of small cell lung cancer (SCLC), highly expressed in a significant fraction of tumors. However, ~25% of human SCLC are ASCL1-low and associated with low neuroendocrine fate and high MYC expression. Using genetically engineered mouse models (GEMMs), we show that alterations in Rb1/Trp53/Myc in the mouse lung induce an ASCL1+ state of SCLC in multiple cells of origin. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation and progression to the NEUROD1+ subtype of SCLC. Surprisingly, ASCL1 loss promotes a SOX9+ mesenchymal/neural crest...
Source: Genes and Development - June 1, 2021 Category: Genetics & Stem Cells Authors: Olsen, R. R., Ireland, A. S., Kastner, D. W., Groves, S. M., Spainhower, K. B., Pozo, K., Kelenis, D. P., Whitney, C. P., Guthrie, M. R., Wait, S. J., Soltero, D., Witt, B. L., Quaranta, V., Johnson, J. E., Oliver, T. G. Tags: Research Papers Source Type: research
Small RNAs guide histone methylation in Arabidopsis embryos [Research Communications]
Epigenetic reprogramming occurs during gametogenesis as well as during embryogenesis to reset the genome for early development. In flowering plants, many heterochromatic marks are maintained in sperm, but asymmetric DNA methylation is mostly lost. Asymmetric DNA methylation is dependent on small RNA but the re-establishment of silencing in embryo is not well understood. Here we demonstrate that small RNAs direct the histone H3 lysine 9 dimethylation during Arabidopsis thaliana embryonic development, together with asymmetric DNA methylation. This de novo silencing mechanism depends on the catalytic domain of SUVH9, a Su(Var...
Source: Genes and Development - June 1, 2021 Category: Genetics & Stem Cells Authors: Parent, J.-S., Cahn, J., Herridge, R. P., Grimanelli, D., Martienssen, R. A. Tags: Research Communications Source Type: research
A myocardin-adjacent lncRNA balances SRF-dependent gene transcription in the heart [Research Communications]
Myocardin, a potent coactivator of serum response factor (SRF), competes with ternary complex factor (TCF) proteins for SRF binding to balance opposing mitogenic and myogenic gene programs in cardiac and smooth muscle. Here we identify a cardiac lncRNA transcribed adjacent to myocardin, named CARDINAL, which antagonizes SRF-dependent mitogenic gene transcription in the heart. CARDINAL-deficient mice show ectopic TCF/SRF-dependent mitogenic gene expression and decreased cardiac contractility in response to age and ischemic stress. CARDINAL forms a nuclear complex with SRF and inhibits TCF-mediated transactivation of the pro...
Source: Genes and Development - June 1, 2021 Category: Genetics & Stem Cells Authors: Anderson, D. M., Anderson, K. M., Nelson, B. R., McAnally, J. R., Bezprozvannaya, S., Shelton, J. M., Bassel-Duby, R., Olson, E. N. Tags: Research Communications Source Type: research
Features and mechanisms of canonical and noncanonical genomic imprinting [Reviews]
Genomic imprinting is the monoallelic expression of a gene based on parent of origin and is a consequence of differential epigenetic marking between the male and female germlines. Canonically, genomic imprinting is mediated by allelic DNA methylation. However, recently it has been shown that maternal H3K27me3 can result in DNA methylation-independent imprinting, termed "noncanonical imprinting." In this review, we compare and contrast what is currently known about the underlying mechanisms, the role of endogenous retroviral elements, and the conservation of canonical and noncanonical genomic imprinting. (Source: Genes and Development)
Source: Genes and Development - June 1, 2021 Category: Genetics & Stem Cells Authors: Hanna, C. W., Kelsey, G. Tags: Chromatin and Gene Expression Reviews Source Type: research
Genetic and biological hallmarks of colorectal cancer [Reviews]
Colorectal cancer has served as a genetic and biological paradigm for the evolution of solid tumors, and these insights have illuminated early detection, risk stratification, prevention, and treatment principles. Employing the hallmarks of cancer framework, we provide a conceptual framework to understand how genetic alterations in colorectal cancer drive cancer cell biology properties and shape the heterotypic interactions across cells in the tumor microenvironment. This review details research advances pertaining to the genetics and biology of colorectal cancer, emerging concepts gleaned from immune and single-cell profil...
Source: Genes and Development - June 1, 2021 Category: Genetics & Stem Cells Authors: Li, J., Ma, X., Chakravarti, D., Shalapour, S., DePinho, R. A. Tags: Cancer and Disease Models Reviews Source Type: research
Winter fields antisense RNAs to kick off flowering [Outlook]
FLOWERING LOCUS C (FLC), a MADS-box transcription factor, plays a major role in determining flowering time in Arabidopsis. In this issue of Genes & Development, Zhao and colleagues (pp. 888–898) elucidate the role of COOLAIR antisense noncoding RNAs in FLC regulation through field trials and laboratory experiments. COOLAIR-mediated FLC silencing is induced by the first seasonal frost in the field and thus acts as a key molecular indicator during autumn for winter arrival. (Source: Genes and Development)
Source: Genes and Development - June 1, 2021 Category: Genetics & Stem Cells Authors: Jin, Y., Marquardt, S. Tags: Plant Biology, Chromatin and Gene Expression Outlook Source Type: research
Corrigendum: FGF signaling regulates development by processes beyond canonical pathways [Errata]
(Source: Genes and Development)
Source: Genes and Development - May 3, 2021 Category: Genetics & Stem Cells Authors: Ray, A. T., Mazot, P., Brewer, J. R., Catela, C., Dinsmore, C. J., Soriano, P. Tags: Errata Source Type: research
Corrigendum: H3.3 actively marks enhancers and primes gene transcription via opening higher-ordered chromatin [Errata]
(Source: Genes and Development)
Source: Genes and Development - May 3, 2021 Category: Genetics & Stem Cells Authors: Chen, P., Zhao, J., Wang, Y., Wang, M., Long, H., Liang, D., Huang, L., Wen, Z., Li, W., Li, X., Feng, H., Zhao, H., Zhu, P., Li, M., Wang, Q.-f., Li, G. Tags: Errata Source Type: research
AGO HITS-CLIP reveals distinct miRNA regulation of white and brown adipose tissue identity [Resource/Methodology]
MicroRNAs (miRNAs) are short, noncoding RNAs that associate with Argonaute (AGO) to influence mRNA stability and translation, thereby regulating cellular determination and phenotype. While several individual miRNAs have been shown to control adipocyte function, including energy storage in white fat and energy dissipation in brown fat, a comprehensive analysis of miRNA activity in these tissues has not been performed. We used high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP) to comprehensively characterize the network of high-confidence, in vivo mRNA:miRNA interactions across white ...
Source: Genes and Development - May 3, 2021 Category: Genetics & Stem Cells Authors: O'Connor, S., Murphy, E. A., Szwed, S. K., Kanke, M., Marchildon, F., Sethupathy, P., Darnell, R. B., Cohen, P. Tags: Resource/Methodology Source Type: research
