Do human transposable element small RNAs serve primarily as genome defenders or genome regulators?

It is currently thought that small RNA (sRNA) based repression mechanisms are primarily employed to mitigate the mutagenic threat posed by the activity of transposable elements (TEs). This can be achieved by the sRNA guided processing of TE transcripts via Dicer-dependent (e.g., siRNA) or Dicer-independent (e.g., piRNA) mechanisms. For example, potentially active human L1 elements are silenced by mRNA cleavage induced by element encoded siRNAs, leading to a negative correlation between element mRNA and siRNA levels. On the other hand, there is emerging evidence that TE derived sRNAs can also be used to regulate the host genome. Here, we evaluated these two hypotheses for human TEs by comparing the levels of TE derived mRNA and TE sRNA across six tissues. The genome defense hypothesis predicts a negative correlation between TE mRNA and TE sRNA levels, whereas the genome regulatory hypothesis predicts a positive correlation. On average, TE mRNA and TE sRNA levels are positively correlated across human tissues. These correlations are higher than seen for human genes or for randomly permuted control data sets. Overall, Alu subfamilies show the highest positive correlations of element mRNA and sRNA levels across tissues, although a few of the youngest, and potentially most active, Alu subfamilies do show negative correlations. Thus, Alu derived sRNAs may be related to both genome regulation and genome defense. These results are inconsistent with a simple model whereby TE derived sRNAs reduce levels of standing TE mRNA via transcript cleavage, and suggest that human cells efficiently process TE transcripts into sRNA based on the available message levels. This may point to a widespread role for processed TE transcripts in genome regulation or to alternative roles of TE-to-sRNA processing including the mitigation of TE transcript cytotoxicity

Piwi Is Required to Limit Exhaustion of Aging Somatic Stem Cells

Please see the graphical abstract in the supplemental files

A Gibbs sampling strategy applied to the mapping of ambiguous short-sequence tags

Motivation: Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) is widely used in biological research. ChIP-seq experiments yield many ambiguous tags that can be mapped with equal probability to multiple genomic sites. Such ambiguous tags are typically eliminated from consideration resulting in a potential loss of important biological information

Transcriptional profiling of interleukin-2-primed human adipose derived mesenchymal stem cells revealed dramatic changes in stem cells response imposed by replicative senescence

Inflammation is a double-edged sword with both detrimental and beneficial consequences. Understanding of the mechanisms of crosstalk between the inflammatory milieu and human adult mesenchymal stem cells is an important basis for clinical efforts. Here, we investigate changes in the transcriptional response of human adipose-derived stem cells to physiologically relevant levels of IL-2 (IL-2 priming) upon replicative senescence. Our data suggest that replicative senescence might dramatically impede human mesenchymal stem cell (MSC) function via global transcriptional deregulation in response to IL-2. We uncovered a novel senescence-associated transcriptional signature in human adipose-derived MSCs hADSCs after exposure to pro-inflammatory environment: significant enhancement of the expression of the genes encoding potent growth factors and cytokines with anti-inflammatory and migration-promoting properties, as well as genes encoding angiogenic and antiapoptotic promoting factors, all of which could participate in the establishment of a unique microenvironment. We observed transcriptional up-regulation of critical components of the nitric oxide synthase pathway (iNOS) in hADSCs upon replicative senescence suggesting, that senescent stem cells can acquire metastasis-promoting properties via stem cell-mediated immunosuppression. Our study highlights the importance of age as a factor when designing cell-based or pharmacological therapies for older patients and predicts measurable biomarkers characteristic of an environment that is conducive to cancer cells invasiveness and metastasis.LM and BGG was supported by grants from the Spanish Ministry of Science and Innovation (SAF 2010-15239) to BGG and. LMP are supported by FPI fellowships from the Spanish Ministry, and BGG acknowledges support from the ``Ramon y Cajal´´ tenure track programme from the Spanish Ministry of Science and Innovation (RYC2009-04669). AS and AA are fellows of Bolashak International Scholarship, AA, AN, AS are sponsored by KazNMU sponsored program.S

Opposing activities of oncogenic MIR17HG and tumor suppressive MIR100HG clusters and their gene targets regulate replicative senescence in human adult stem cells.

Growing evidence suggests that many diseases of aging, including diseases associated with robust changes and adipose deports, may be caused by resident adult stem cell exhaustion due to the process called cellular senescence. Understanding how microRNA pathways can regulate cellular senescence is crucial for the development of novel diagnostic and therapeutic strategies to combat these pathologies. Herein, using integrated transcriptomic and semi-quantitative proteomic analysis, we provide a system level view of the regulation of human adipose-derived stem cell senescence by a subset of mature microRNAs (termed senescence-associated-microRNAs) produced by biogenesis of oncogenic MIR17HG and tumor-suppressive MIR100HG clusters. We demonstrate functional significance of these mature senescence-associated-microRNAs in the process of replicative senescence of human adipose-derived stem cells ex-vivo and define a set of senescence-associated-microRNA gene targets that are able to elicit, modulate and, most importantly, balance intimate connections between oncogenic and senescent events

Mesenchymal Stem Cells Secretory Responses: Senescence Messaging Secretome and Immunomodulation Perspective

Mesenchymal stem/stromal cells (MSC) have been tested in a significant number of clinical trials, where they exhibit regenerative and repair properties directly through their differentiation into the cells of the mesenchymal origin or by modulation of the tissue/organ microenvironment. Despite various clinical effects upon transplantation, the functional properties of these cells in natural settings and their role in tissue regeneration in vivo is not yet fully understood. The omnipresence of MSC throughout vascularized organs equates to a reservoir of potentially therapeutic regenerative depots throughout the body. However, these reservoirs could be subjected to cellular senescence. In this review, we will discuss current progress and challenges in the understanding of different biological pathways leading to senescence. We set out to highlight the seemingly paradoxical property of cellular senescence: its beneficial role in the development and tissue repair and detrimental impact of this process on tissue homeostasis in aging and disease. Taking into account the lessons from the different cell systems, this review elucidates how autocrine and paracrine properties of senescent MSC might impose an additional layer of complexity on the regulation of the immune system in development and disease. New findings that have emerged in the last few years could shed light on sometimes seemingly controversial results obtained from MSC therapeutic applications

Developmental Changes in the Sciara II/9A Initiation Zone for DNA Replication

Developmentally regulated initiation of DNA synthesis was studied in the fly Sciara at locus II/9A. PCR analysis of nascent strands revealed an initiation zone that spans ∼8 kb in mitotic embryonic cells and endoreplicating salivary glands but contracts to 1.2 to 2.0 kb during DNA amplification of DNA puff II/9A. Thus, the amplification origin occurs within the initiation zone used for normal replication. The initiation zone left-hand border is constant, but the right-hand border changes during development. Also, there is a shift in the preferred site for initiation of DNA synthesis during DNA amplification compared to that in preamplification stages. This is the first demonstration that once an initiation zone is defined in embryos, its borders and preferred replication start sites can change during development. Chromatin immunoprecipitation showed that the RNA polymerase II 140-kDa subunit occupies the promoter of gene II/9-1 during DNA amplification, even though intense transcription will not start until the next developmental stage. RNA polymerase II is adjacent to the right-hand border of the initiation zone at DNA amplification but not at preamplification, suggesting that it may influence the position of this border. These findings support a relationship between the transcriptional machinery and establishment of the replication initiation zone