ClinSV: clinical grade structural and copy number variant detection from whole genome sequencing data.

Whole genome sequencing (WGS) has the potential to outperform clinical microarrays for the detection of structural variants (SV) including copy number variants (CNVs), but has been challenged by high false positive rates. Here we present ClinSV, a WGS based SV integration, annotation, prioritization, and visualization framework, which identified 99.8% of simulated pathogenic ClinVar CNVs > 10 kb and 11/11 pathogenic variants from matched microarrays.

Subcellular relocalization and nuclear redistribution of the RNA methyltransferases TRMT1 and TRMT1L upon neuronal activation.

RNA modifications are dynamic chemical entities that expand the RNA lexicon and regulate RNA fate. The most abundant modification present in mRNAs, N6-methyladenosine (mA), has been implicated in neurogenesis and memory formation. However, whether additional RNA modifications may be playing a role in neuronal functions and in response to environmental queues is largely unknown.

Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is common, with a prevalence of 1/1000 and predominantly caused by disease-causing variants in PKD1 or PKD2. Clinical diagnosis is usually by age-dependent imaging criteria, which is challenging in patients with atypical clinical features, without family history, or younger age. However, there is increasing need for definitive diagnosis of ADPKD with new treatments available.

Adar3 Is Involved in Learning and Memory in Mice.

The amount of regulatory RNA encoded in the genome and the extent of RNA editing by the post-transcriptional deamination of adenosine to inosine (A-I) have increased with developmental complexity and may be an important factor in the cognitive evolution of animals. The newest member of the A-I editing family of ADAR proteins, the vertebrate-specific ADAR3, is highly expressed in the brain, but its functional significance is unknown. studies have suggested that ADAR3 acts as a negative regulator of A-I RNA editing but the scope and underlying mechanisms are also unknown.

The RNA modification landscape in human disease.

RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has changed dramatically in recent years, to a large extent as a result of systematic efforts to map and quantify various RNA modifications in a transcriptome-wide manner, revealing that RNA modifications are reversible, dynamically regulated, far more widespread than originally thought, and involved in major biological processes, including cell differentiation, sex determination, and stress responses. Here we summarize the state of knowledge and provide a catalog of RNA modifications and their links to neurological disorders, cancers, and other diseases.

Analysis of steric effects in DamID profiling of transcription factor target genes.

DNA adenine methyltransferase identification (DamID) is an enzymatic technology for detecting DNA regions targeted by chromatin-associated proteins. Proteins are fused to bacterial DNA adenine methyltransferase (Dam) and expressed in cultured cells or whole organisms. Here, we used DamID to detect DNA regions bound by the cardiac-restricted transcription factors (TFs) NKX2-5 and SRF, and ubiquitously-expressed co-factors ELK1 and ELK4.

Seq and You Will Find.

The human genome sequence is freely available, nearly complete and is providing a foundation of research opportunities that are overturning our current understanding of human biology. The advent of next generation sequencing has revolutionized the way we can interrogate the genome and its transcriptional products and how we analyze, diagnose, monitor and even treat human disease. Personal genetic profiles are increasing dramatically in medical value as researchers accumulate more and more knowledge about the interaction between genetic and environmental factors that contribute to the onset of common disorders.

NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets.

We take a functional genomics approach to congenital heart disease mechanism. We used DamID to establish a robust set of target genes for NKX2-5 wild type and disease associated NKX2-5 mutations to model loss-of-function in gene regulatory networks. NKX2-5 mutants, including those with a crippled homeodomain, bound hundreds of targets including NKX2-5 wild type targets and a unique set of "off-targets", and retained partial functionality.

Long noncoding RNAs in cardiac development and pathophysiology.

Heart function requires sophisticated regulatory networks to orchestrate organ development, physiological responses, and environmental adaptation. Until recently, it was thought that these regulatory networks are composed solely of protein-mediated transcriptional control and signaling systems; consequently, it was thought that cardiac disease involves perturbation of these systems. However, it is becoming evident that RNA, long considered to function primarily as the platform for protein production, may in fact play a major role in most, if not all, aspects of gene regulation, especially the epigenetic processes that underpin organogenesis.

Decoding the non-coding RNAs in Alzheimer's disease.

Non-coding RNAs (ncRNAs) are integral components of biological networks with fundamental roles in regulating gene expression. They can integrate sequence information from the DNA code, epigenetic regulation and functions of multimeric protein complexes to potentially determine the epigenetic status and transcriptional network in any given cell. Humans potentially contain more ncRNAs than any other species, especially in the brain, where they may well play a significant role in human development and cognitive ability.

MicroRNA networks surrounding APP and amyloid-β metabolism--implications for Alzheimer's disease.

MicroRNAs (miRNAs) are small non-coding RNA regulators of protein synthesis that function as "fine-tuning" tools of gene expression in development and tissue homeostasis. Their profiles are significantly altered in neurodegenerative diseases such as Alzheimer's disease (AD) that is characterized by both amyloid-β (Aβ) and tau deposition in brain. A key challenge remains in determining how changes in miRNA profiles translate into biological function in a physiological and pathological context.

Target gene repression mediated by miRNAs miR-181c and miR-9 both of which are down-regulated by amyloid-β.

MicroRNAs (miRNAs) are small non-coding RNA regulators of protein synthesis that are essential for normal brain development and function. Their profiles are significantly altered in neurodegenerative diseases such as Alzheimer's disease (AD) that is characterized by amyloid-β (Aβ) and tau deposition in brain. How deregulated miRNAs contribute to AD is not understood, as their dysfunction could be both a cause and a consequence of disease.

Neuronal microRNA deregulation in response to Alzheimer's disease amyloid-beta.

Normal brain development and function depends on microRNA (miRNA) networks to fine tune the balance between the transcriptome and proteome of the cell. These small non-coding RNA regulators are highly enriched in brain where they play key roles in neuronal development, plasticity and disease. In neurodegenerative disorders such as Alzheimer's disease (AD), brain miRNA profiles are altered; thus miRNA dysfunction could be both a cause and a consequence of disease.

Arabidopsis MSI1 is required for negative regulation of the response to drought stress.

Arabidopsis MSI1 has fundamental functions in plant development. MSI1 is a subunit of Polycomb group protein complexes and Chromatin assembly factor 1, and it interacts with the Retinoblastoma-related protein 1. Altered levels of MSI1 result in pleiotropic phenotypes, reflecting the complexity of MSI1 protein functions.

Alzheimer's disease selective vulnerability and modeling in transgenic mice.

Neurodegenerative diseases are characterized by 'hot spots' of degeneration. The regions of primary vulnerability vary between different neurodegenerative diseases. Within these regions, some neurons are lost whereas others that are morphologically indiscriminate survive.

An update on the toxicity of Abeta in Alzheimer's disease.

Alzheimer's disease is characterized histopathologically by deposition of insoluble forms of the peptide Abeta and the protein tau in brain. Abeta is the principal component of amyloid plaques and tau of neurofibrillary tangles. Familial cases of AD are associated with causal mutations in the gene encoding the amyloid precursor protein, APP, from which the amyloidogenic Abeta peptide is derived, and this supports a role for Abeta in disease.

Is tau aggregation toxic or protective: a sensible question in the absence of sensitive methods?

In Alzheimer's disease brain, the microtubule-associated protein tau detaches from the microtubules, pathologically interacts with cellular proteins, and eventually forms insoluble aggregates that also bind and trap a myriad of proteins. As these proteins are depleted from the cellular pool, they are unavailable for physiological functions. Thus elevated tau levels are pathogenic, even in the absence of tau aggregation.

Functional genomics dissects pathomechanisms in tauopathies: mitosis failure and unfolded protein response.

Background: Alzheimer's disease (AD) is characterized by beta-amyloid (Abeta) peptide-containing plaques and tau-containing neurofibrillary tangles. By intracerebral injection of Abeta(42), both pathologies have been combined in P301L tau mutant mice. Furthermore, in cell culture, Abeta(42) induces tau aggregation.

A decade of tau transgenic animal models and beyond.

The first tau transgenic mouse model was established more than a decade ago. Since then, much has been learned about the role of tau in Alzheimer's disease and related disorders. Animal models, both in vertebrates and invertebrates, were significantly improved and refined as a result of the identification of pathogenic mutations in Tau in human cases of frontotemporal dementia.

Chromatin assembly factor CAF-1 is required for cellular differentiation during plant development.

Chromatin assembly factor CAF-1 facilitates the formation of nucleosomes on newly replicated DNA in vitro. However, the role of CAF-1 in development is poorly understood because mutants are not available in most multicellular model organisms. Biochemical evidence suggests that FASCIATA1, FASCIATA2 and MSI1 form CAF-1 in Arabidopsis thaliana.

Alzheimer's disease and frontotemporal dementia: prospects of a tailored therapy?

Alzheimer's disease (AD) is the most prevalent dementia (accounting for 50%-75% of cases of dementia in people aged over 65 years), followed by frontotemporal dementia (FTD) (10%-20% of cases). AD is characterised histopathologically by Abeta-containing amyloid plaques and tau-containing neurofibrillary tangles, whereas FTD exhibits neurofibrillary tangles alone. Current symptomatic treatments of AD are of limited benefit, as they are not directed at the underlying biological basis of the disease.

Polycomb-group proteins repress the floral activator AGL19 in the FLC-independent vernalization pathway.

Polycomb-group (PcG) proteins form a cellular memory by maintaining developmental regulators in a transcriptionally repressed state. We identified a novel flowering gene that is under PcG control in Arabidopsis--the MADS-box gene AGL19. AGL19 expression is maintained at very low levels by the PcG proteins MSI1, CLF, and EMF2, and AGL19 is partly responsible for the early flowering phenotype of clf mutants.

Regulation of flowering time by Arabidopsis MSI1.

The transition to flowering is tightly controlled by endogenous programs and environmental signals. We found that MSI1 is a novel flowering-time gene in Arabidopsis. Both partially complemented msi1 mutants and MSI1 antisense plants were late flowering, whereas ectopic expression of MSI1 accelerated flowering.

Functional genomic analysis of CAF-1 mutants in Arabidopsis thaliana.

Duplication of chromatin following DNA replication requires spatial reorganization of chromatin domains assisted by chromatin assembly factor CAF-1. Here, we tested the genomic consequences of CAF-1 loss and the function of chromatin assembly factor CAF-1 in heterochromatin formation. Genes located in heterochromatic regions are usually silent, and we found that this transcriptional repression persists in the absence of CAF-1 in Arabidopsis.