Inference of RNA decay rate from transcriptional profiling highlights the regulatory programs of Alzheimer's disease.

The abundance of mRNA is mainly determined by the rates of RNA transcription and decay. Here, we present a method for unbiased estimation of differential mRNA decay rate from RNA-sequencing data by modeling the kinetics of mRNA metabolism. We show that in all primary human tissues tested, and particularly in the central nervous system, many pathways are regulated at the mRNA stability level. We present a parsimonious regulatory model consisting of two RNA-binding proteins and four microRNAs that modulate the mRNA stability landscape of the brain, which suggests a new link between RBFOX proteins and Alzheimer's disease. We show that downregulation of RBFOX1 leads to destabilization of mRNAs encoding for synaptic transmission proteins, which may contribute to the loss of synaptic function in Alzheimer's disease. RBFOX1 downregulation is more likely to occur in older and female individuals, consistent with the association of Alzheimer's disease with age and gender."mRNA abundance is determined by the rates of transcription and decay. Here, the authors propose a method for estimating the rate of differential mRNA decay from RNA-seq data and model mRNA stability in the brain, suggesting a link between mRNA stability and Alzheimer's disease.

Systematic discovery of structural elements governing stability of mammalian messenger RNAs.

Decoding post-transcriptional regulatory programs in RNA is a critical step towards the larger goal of developing predictive dynamical models of cellular behaviour. Despite recent efforts, the vast landscape of RNA regulatory elements remains largely uncharacterized. A long-standing obstacle is the contribution of local RNA secondary structure to the definition of interaction partners in a variety of regulatory contexts, including--but not limited to--transcript stability, alternative splicing and localization. There are many documented instances where the presence of a structural regulatory element dictates alternative splicing patterns (for example, human cardiac troponin T) or affects other aspects of RNA biology. Thus, a full characterization of post-transcriptional regulatory programs requires capturing information provided by both local secondary structures and the underlying sequence. Here we present a computational framework based on context-free grammars and mutual information that systematically explores the immense space of small structural elements and reveals motifs that are significantly informative of genome-wide measurements of RNA behaviour. By applying this framework to genome-wide human mRNA stability data, we reveal eight highly significant elements with substantial structural information, for the strongest of which we show a major role in global mRNA regulation. Through biochemistry, mass spectrometry and in vivo binding studies, we identified human HNRPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1, also known as HNRNPA2B1) as the key regulator that binds this element and stabilizes a large number of its target genes. We created a global post-transcriptional regulatory map based on the identity of the discovered linear and structural cis-regulatory elements, their regulatory interactions and their target pathways. This approach could also be used to reveal the structural elements that modulate other aspects of RNA behaviour

Investigating the Role of Muscleblind-Like 1 in the Suppression of Breast Cancer Progression

Breast cancer is a prevalent disease. Metastatic disease accounts for the majority of deaths from breast cancer, as patients with distant metastatic disease have a much worse prognosis than those with localized disease. In order to better understand why some breast cancers metastasize and others do not, it is critical to identify and elucidate the determinants of breast cancer progression. Post-transcriptional control of gene expression plays a central role in modulating transcriptional output. The interactions between messenger RNA cis-regulatory elements and trans-factors control coordinated gene expression states. Posttranscriptional regulatory programs that enhance metastatic capacity are selected for during cancer progression. In this study, the RNA binding protein Muscleblind-like 1 (MBNL1) is identified as a novel suppressor of breast cancer metastasis. MBNL1 loss-of-function contributes to the pathogenesis of myotonic dystrophy, a human genetic disease, but has no reported role in tumorigenesis or cancer progression. In this study, MBNL1 is identified as a suppressor of breast cancer metastasis. MBNL1 was found to suppress metastasis of human breast cancer cells in a xenograft mouse model. Additionally, MBNL1 transcript levels are significantly correlated with metastasis-free survival of breast cancer patients. MBNL1 depletion was also found to enhance the invasion and trans-endothelial migration capacity of breast cancer cells. Identification of endogenous MBNL1 protein-RNA interactions in breast cancer cells was carried out using HITS-CLIP. Transcriptome-wide analysis of MBNL1-dependent transcript stability and MBNL1 HITS-CLIP data revealed that globally, transcripts directly bound by MBNL1 are stabilized by MBNL1. Two transcripts, DBNL and TACC1, were identified as transcripts that were bound by MBNL1 and also destabilized upon MBNL1 depletion. Both DBNL and TACC1, when overexpressed in breast cancer cells depleted of MBNL1, were found to reverse the pro-invasive and metastatic colonization phenotypes observed upon MBNL1 depletion. Therefore, DBNL and TACC1 were identified as modulators of the metastasis suppressive effect of MBNL1 in breast cancer

Randomized trial of DVD, telephone, and usual care for increasing mammography adherence

The purpose of this study was to test an intervention to increase mammography screening in women 51-75 years of age who had not received a mammogram in the last 15 months. A total of 1681 women were randomized to (1) a mailed tailored interactive DVD, (2) a computer-tailored telephone counseling, or (3) usual care. Women with income below US$75,000 who were in the interactive DVD group had significantly more mammograms than women in usual care. Women with income above US$75,000 had significantly fewer mammograms than women with income less than US$75,000 regardless of group. Further investigation is needed to understand why women with income above US$75,000 did not show the same benefit of the intervention

Cancer cells exploit an orphan RNA to drive metastatic progression.

Here we performed a systematic search to identify breast-cancer-specific small noncoding RNAs, which we have collectively termed orphan noncoding RNAs (oncRNAs). We subsequently discovered that one of these oncRNAs, which originates from the 3' end of TERC, acts as a regulator of gene expression and is a robust promoter of breast cancer metastasis. This oncRNA, which we have named T3p, exerts its prometastatic effects by acting as an inhibitor of RISC complex activity and increasing the expression of the prometastatic genes NUPR1 and PANX2. Furthermore, we have shown that oncRNAs are present in cancer-cell-derived extracellular vesicles, raising the possibility that these circulating oncRNAs may also have a role in non-cell autonomous disease pathogenesis. Additionally, these circulating oncRNAs present a novel avenue for cancer fingerprinting using liquid biopsies

Publisher Correction: Inference of RNA decay rate from transcriptional profiling highlights the regulatory programs of Alzheimer’s disease

The original version of this Article contained an error in Figure 3, where panel d was inadvertently replaced with a duplicate of panel c during typesetting. Also, the legend of Figure 5f incorrectly read '310 AD patients (blue dots, r = -0.4) and 157 non-demented individuals (green dots, r = -0.1)', and should have read '310 AD patients (blue dots, r = -0.1) and 157 non-demented individuals (green dots, r = -0.4)'. Both of these errors have now been corrected in both the PDF and HTML versions of the Article

Primary Cutaneous Melanoma Arising in a Long-Standing Irradiated Keloid

Ionizing radiation has been used therapeutically for a variety of clinical conditions, including treatment of hypertrophic keloids. Keloids may rarely be associated with malignancy, but the use of low-dose ionizing radiation is associated with an increased risk of cutaneous malignancies. We describe a case in which a primary desmoplastic melanoma arose in a long-standing, previously irradiated keloid

Human Rights in the Context of Environmental Conservation on the US-Mexico Border

At Cabeza Priesta National Wildlife Refuge, a wilderness area on the US-Mexico border in Arizona, conflicting policies permit the provision of supplementary water for wildlife but not for undocumented immigrants passing through the area. Federal refuge environmental policy prioritizes active management of endangered and threatened species. Vast systems of water resources have been developed to support wildlife conservation in this extremely hot and dry environment. At the same time, humanitarian groups are not allowed to supply water to undocumented border crossers in the park. Human border-crossers must utilize non-potable wildlife water guzzlers for survival and face risk of illness or death by dehydration. This article analyzes human rights via an ethnographic lens. From this perspective, water policy at the wildlife refuge brings into question the value of human life in a border conservation context, especially for those entering the site illegally

Planting the Seed: Using Research As a Tool to Revitalize Puberty Ceremonies in Anishinaabe Communities

Purpose: The purpose of this work is to honor the wisdoms of Anishinaabe Elders, community and culture by interweaving these teachings with my own (first author) Anishinaabe experiences and a research project. Ceremonies are an important health practice for Anishinaabe people. This project aimed to gain a clearer conceptualization of the protective role of Anishinaabe puberty ceremonies on health in adolescence and across the lifespan. Design/methodology/approach Spiritual offerings guided this project at every stage including inviting Elders and community members into shared spaces of storytelling and teaching elicitation and grounding me as I carefully adopted the use of a western tool (research) in sacred community spaces. Elders were invited to share their experiences and perspectives. Three community members engaged with the interview transcripts on their own before coming together to discuss themes, patterns and insights that arose for them. This group coding discussion constructed the structural foundation of the findings. Findings: An Anishinaabe perspective on youth development emerged. Key aspects of this model included a foundation of ceremonial experiences that spiritually prepares a child for adulthood and impending life’s challenges. As one transitions into adulthood, they accept the responsibilities of being caretakers of their families and communities and gain new tools to contribute to Anishinaabe society. Ideally, this society prioritizes Anishinaabe spirituality, language and way of life. Originality/value Frameworks of health, grounded in unique community wisdoms and worldviews, are imperative to repair spiritual and community relationships damaged in a history of colonialism. An Anishinaabe perspective on youth development may shed light on shared Indigenous experiences of cultural restoration and continuity