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Current Opinion in Genetics & Development

Christian J Braun, Michael T Hemann
RNA molecules are subject to a complex co-transcriptional and post-transcriptional life cycle, controlled at all stages by RNA binding proteins (RBPs) and non-coding RNAs that influence mRNA stability, splicing, localization, and decay. Together with mechanisms regulating the process of transcription itself, non-coding RNAs and RBPs contribute to a model of para-transcriptional coordination of gene expression, which is utilized during normal tissue physiology and cancer development in order to execute complex gene expression programs...
May 20, 2019: Current Opinion in Genetics & Development
Yekaterina A Miroshnikova, Idan Cohen, Elena Ezhkova, Sara A Wickström
The skin epidermis is a constantly renewing stratified epithelium that provides essential protective barrier functions throughout life. Epidermal stratification is governed by a step-wise differentiation program that requires precise spatiotemporal control of gene expression. How epidermal self-renewal and differentiation are regulated remains a fundamental open question. Cell-intrinsic and cell-extrinsic mechanisms that modify chromatin structure and interactions have been identified as key regulators of epidermal differentiation and stratification...
May 18, 2019: Current Opinion in Genetics & Development
Robin H van der Weide, Elzo de Wit
Early in development embryos undergo a transition, during which maternally deposited transcripts are replaced by zygotic transcripts. During this transition the zygotic genome is activated. Recently, the three-dimensional organization of the genome (3D genome) has been charted surrounding this transition phase in a number of species. A common feature of the 3D genome in all these species is that they go through a phase, during which architectural features of the 3D genome, such as TADs and compartments are lost and a uniform chromatin architecture is established...
May 18, 2019: Current Opinion in Genetics & Development
Isabel Guerreiro, Jop Kind
The nuclear lamina (NL) consists of a thin meshwork of lamins and associated proteins that lines the inner nuclear membrane (INM). In metazoan nuclei, a large proportion of the genome contacts the NL in broad lamina-associated domains (LADs). Contacts of the NL with the genome are believed to aid the spatial organization of chromosomes and contribute to the regulation of transcription. Here, we will focus on recent insights in the structural organization of the genome at the NL and the role of this organization in the regulation of gene expression...
May 18, 2019: Current Opinion in Genetics & Development
Isabel Sierra, Montserrat C Anguera
The imbalance of sex chromosomes between females (XX) and males (XY) necessitates strict regulation of X-linked gene expression. X-Chromosome Inactivation (XCI) selects one X for transcriptional silencing in the early embryo, generating an epigenetically distinct and transcriptionally silent X that is maintained into adulthood. Some genes on the inactive X escape XCI, and human somatic cells have a greater number of escape genes compared to mice. Advances with single-cell technologies have revealed human-specific escape genes in fibroblasts and immune cells, some of which exhibit cell and tissue specificity...
May 17, 2019: Current Opinion in Genetics & Development
Ángela Sedeño Cacciatore, Benjamin D Rowland
From the dynamic interphase genome to compacted mitotic chromosomes, DNA is organized by the conserved SMC complexes cohesin and condensin. The picture is emerging that these complexes structure the genome through a shared basic principle that involves the formation and processive enlargement of chromatin loops. This appears to be an asymmetric process, in which the complex anchors at the base of a loop and then enlarges the loop in a one-sided manner. We discuss the latest insights into how ATPase-driven conformational changes within these complexes may enlarge loops, and consider how asymmetric DNA reeling can bring together genomic elements in a symmetric manner...
May 17, 2019: Current Opinion in Genetics & Development
Dario Nicetto, Kenneth S Zaret
Compacted, transcriptionally repressed chromatin, referred to as heterochromatin, represents a major fraction of the higher eukaryotic genome and exerts pivotal functions of silencing repetitive elements, maintenance of genome stability, and control of gene expression. Among the different histone post-translational modifications (PTMs) associated with heterochromatin, tri-methylation of lysine 9 on histone H3 (H3K9me3) is gaining increased attention. Besides its known role in repressing repetitive elements and non-coding portions of the genome, recent observations indicate H3K9me3 as an important player in silencing lineage-inappropriate genes...
May 16, 2019: Current Opinion in Genetics & Development
Camille Boutin, Laurent Kodjabachian
Multiciliated cells (MCCs) are specialized in fluid propulsion through directional beating of myriads of superficial motile cilia, which rest on modified centrioles named basal bodies. MCCs are found throughout metazoans, and serve functions as diverse as feeding and locomotion in marine organisms, as well as mucus clearance, cerebrospinal fluid circulation, and egg transportation in mammals. Impaired MCC differentiation or activity causes diseases characterized by severe chronic airway infections and reduced fertility...
May 15, 2019: Current Opinion in Genetics & Development
Chiara Falcomatà, Stefanie Bärthel, Günter Schneider, Dieter Saur, Christian Veltkamp
Molecular profiling of cancer patients and modelling of human cancer in mice revealed cell type and tissue-specific differences in tumor development and evolution. However, the context-dependent determinants of cancer remain poorly understood. A systematic characterization of the biological underpinnings of context-specificity will, therefore, be pivotal to design more effective therapies. In this review article, we focus on recent advances on molecular, cellular and microenvironmental aspects of context-dependency...
May 8, 2019: Current Opinion in Genetics & Development
Julia Weber, Roland Rad
Gene targeting in mammals has revolutionized the study of complex diseases, involving the interaction of multiple genes, cells, and organ systems. In cancer, genetically engineered mouse models deciphered biological principles by integrating molecular mechanisms, cellular processes, and environmental signals. Major advances in manipulative mouse genetics are currently emerging from breakthroughs in gene editing, which open new avenues for rapid model generation. Here, we review recent developments in engineering CRISPR mouse models of cancer...
May 8, 2019: Current Opinion in Genetics & Development
Faisal T Basheer, George S Vassiliou
Acute myeloid leukemia (AML) is an aggressive cancer that remains lethal to the majority of sufferers. Whilst the mainstay treatments for this condition have remained largely unchanged over the past five decades, progress in deciphering its pathogenesis has accelerated in recent years, propelled in part by advances in cancer genomics and mechanistic studies of leukemogenic mutations. Newer molecular therapies targeting aberrant biological pathways are currently under investigation with a few moving closer to clinical use...
May 4, 2019: Current Opinion in Genetics & Development
Luisa Henkel, Benedikt Rauscher, Michael Boutros
Genetic co-dependencies have been found in many contexts, from processes during the development of organisms to many diseases in man, including cancer. Genetic interactions - and in particular synthetic lethal phenotypes - have provided fundamental insights into the genetic architecture of cells and identified potential new opportunities for therapeutic interventions. However, recent studies also demonstrated that genetic interactions are highly context dependent and synthetic lethal interactions in one tumor context might not be translatable to others...
April 23, 2019: Current Opinion in Genetics & Development
Barbara Mair, Jason Moffat, Charles Boone, Brenda J Andrews
The genotype-to-phenotype relationship in health and disease is complex and influenced by both an individual's environment and their unique genome. Personal genetic variants can modulate gene function to generate a phenotype either through a single gene effect or through genetic interactions involving two or more genes. The relevance of genetic interactions to disease phenotypes has been particularly clear in cancer research, where an extreme genetic interaction, synthetic lethality, has been exploited as a therapeutic strategy...
April 8, 2019: Current Opinion in Genetics & Development
Stephen J Pettitt, Christopher J Lord
The poly-(ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib was the first licenced cancer drug that targeted an inherited form of cancer, namely ovarian cancers caused by germline BRCA1 or BRCA2 gene mutations. Multiple different PARPi have now been approved for use in a wider group of gynaecological cancers as well as for the treatment of BRCA-gene mutant breast cancer. Despite these advances, resistance to PARPi is a common clinical phenotype. Understanding, at the molecular level, how tumour cells respond to PARPi has the potential to inform how these drugs should be used clinically and since the discovery of this drug class, multiple different functional genomic strategies have been employed to dissect PARPi sensitivity and resistance...
April 4, 2019: Current Opinion in Genetics & Development
Anirudh Prahallad, Michael Rugaard Jensen, Emilie Anne Chapeau
Acquired resistance is a major limitation for the successful treatment of cancer patients. Although numerous efficacious cancer therapeutics have been developed in the past decades, resistance arises due to a variety of reasons including tumoral genetic alterations, or modulation of factors in the tumor environment. Understanding the mechanistic reasons for tumor relapse supports the identification of novel combination therapies that could lead to more durable responses. Here, we will review large-scale in vivo screens in pre-clinical cancer models that employed genetic and pharmacological agents toward elucidating acquired drug resistance and informing on beneficial combinations to be tested in clinical trials...
April 3, 2019: Current Opinion in Genetics & Development
Matthias Hinterndorfer, Johannes Zuber
Drug development remains a slow and expensive process, while the effective use of established therapeutics is widely hampered by our limited understanding of response and resistance mechanisms. Functional-genetic tools such as CRISPR/Cas9, advanced RNAi methods, and targeted protein degradation, together with other emerging technologies such as time-resolved and single-cell transcriptomics, fundamentally change the way we can search for candidate therapeutic targets and evaluate them before drug development...
April 2, 2019: Current Opinion in Genetics & Development
Yuen-Yi Tseng, Jesse S Boehm
Precision cancer medicine is based on the ability to predict the dependencies of a given tumor from its molecular makeup. These dependencies can be exploited with targeted, cytotoxic and/or immunity-inducing therapeutics. Ongoing efforts to perform genomic and cellular analyses on clinically annotated patient tumors are powerful, but bounded to existing therapies and focused cohorts. Here, we describe how living tumor material is increasingly being used in the generation of a systematic laboratory-based functional map of cancer dependencies (a 'Cancer Dependency Map')...
March 28, 2019: Current Opinion in Genetics & Development
Maja Kneissig, Sara Bernhard, Zuzana Storchova
Cancer cells differ from healthy cells by genetic information that is massively altered not only by point mutations and small insertions and deletions, but also by large scale changes such as chromosomal rearrangements as well as gains and losses of individual chromosomes or entire chromosome sets. How exactly large-scale chromosomal abnormalities contribute to tumorigenesis has been difficult to study. Remarkable progress has been recently made thanks to in vitro models that mimic large-scale chromosomal aberrations and allow their systematic analysis...
March 25, 2019: Current Opinion in Genetics & Development
Amaia Lujambio, Ana Banito
Cellular senescence is implicated in numerous biological processes, and can play pleiotropic, sometimes opposing, roles in cancer. Several triggers, cell types, contexts, and senescence-associated phenotypes introduce a multitude of possibilities when studying this process and its biological consequences. Recent studies continue to characterize cellular senescence at different levels, using a combination of functional screens, in silico analysis, omics characterizations and more targeted studies. However, a comprehensive analysis of its context-dependent effects and multiple phenotypes is required...
March 13, 2019: Current Opinion in Genetics & Development
Ultan McDermott
In the last decade, we have witnessed tremendous advances in our understanding of the landscape of the molecular alterations that underpin many of the most prevalent cancers, in the use of automated high throughput platforms for high-throughput drug screens in cancer cells, in the creation of more clinically relevant cancer cell models, in the application of CRISPR genetic screens for novel target identification, and lastly in the development of more useful computational approaches in the pursuit of biomarkers of drug response...
March 7, 2019: Current Opinion in Genetics & Development
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