Hyeshik Chang

Nature Structural & Molecular Biology 20, 789 (2013). doi:10.1038/nsmb.2606

Authors: Peter Smibert, Jr-Shiuan Yang, Ghows Azzam, Ji-Long Liu & Eric C Lai

by Peng Jiang, Mona Singh, Hilary A. Coller

Transcript degradation is a widespread and important mechanism for regulating protein abundance. Two major regulators of transcript degradation are RNA Binding Proteins (RBPs) and microRNAs (miRNAs). We computationally explored whether RBPs and miRNAs cooperate to promote transcript decay. We defined five RBP motifs based on the evolutionary conservation of their recognition sites in 3′UTRs as the binding motifs for Pumilio (PUM), U1A, Fox-1, Nova, and UAUUUAU. Recognition sites for some of these RBPs tended to localize at the end of long 3′UTRs. A specific group of miRNA recognition sites were enriched within 50 nts from the RBP recognition sites for PUM and UAUUUAU. The presence of both a PUM recognition site and a recognition site for preferentially co-occurring miRNAs was associated with faster decay of the associated transcripts. For PUM and its co-occurring miRNAs, binding of the RBP to its recognition sites was predicted to release nearby miRNA recognition sites from RNA secondary structures. The mammalian miRNAs that preferentially co-occur with PUM binding sites have recognition seeds that are reverse complements to the PUM recognition motif. Their binding sites have the potential to form hairpin secondary structures with proximal PUM binding sites that would normally limit RISC accessibility, but would be more accessible to miRNAs in response to the binding of PUM. In sum, our computational analyses suggest that a specific set of RBPs and miRNAs work together to affect transcript decay, with the rescue of miRNA recognition sites via RBP binding as one possible mechanism of cooperativity.

Biochemistry: Rear view of an enzyme

Nature 497, 7451 (2013). doi:10.1038/nature12249

Authors: Mary Dasso

The enzyme Ubc9 mediates attachment of the small modifier protein SUMO to target proteins. It emerges that for optimal functioning — and for proper meiotic cell division — Ubc9 itself must be modified by SUMO.

MicroRNAs (miRNAs) are key mediators of post-transcriptional gene regulation. The miRNA precursors are processed by the endonucleases Drosha and Dicer into a duplex, bound to an Argonaute protein and unwound into two single-stranded miRNAs. Although alternative ways to generate miRNAs have been discovered, e.g. pre-miRNA cleavage by Ago2 or cleavage products of snoRNAs or tRNAs, all known pathways converge on a double-stranded RNA duplex. Exogenous single-stranded siRNAs (ss-siRNAs) can elicit an effective RNA interference reaction; recent studies have identified chemical modifications increasing their stability and activity. Here, we provide first evidence that endogenous, unmodified, single-stranded RNA sequences are generated from single-stranded loop regions of human pre-miRNA hairpins, the so called loop-miRs. Luciferase assays and immunoprecipitation validate loop-miR activity and incorporation into RNA-induced silencing complexes. This study identifies endogenous miRNAs that are generated from single-stranded regions; hence, it provides evidence that precursor-miRNAs can give rise to three distinct endogenous miRNAs: the guide strand, the passenger strand and the loop-miR.

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Methods for validation of miRNA sequence variants and the cleavage of their targets.

Methods. 2012 Oct;58(2):135-43

Authors: Jeong DH, Green PJ

Abstract
MicroRNA (miRNA) variants that share the sequences with other closely related miRNAs have been identified by deep sequencing and have been implicated in the diverse regulation of their target genes. The miRNA variants that originate from the same miRNA precursor are among the most common and have been termed "isomiRs." IsomiRs can be generated by several mechanisms such as differential processing by DICER, RNA degradation, or RNA editing. Members of the same miRNA family that have distinct sequences also contribute to the diversity of miRNA variants. Although many miRNA variants are lowly expressed and may function redundantly with their reference miRNAs, some miRNA variants are highly and/or differentially expressed. In addition, slight differences in sequence among miRNA variants can affect their specificity in target selection. Here, we describe two methods for detecting or validating miRNA variants and the target events they mediate.

PMID: 22922269 [PubMed - indexed for MEDLINE]

MicroRNA target site identification by integrating sequence and binding information.

Nat Methods. 2013 May 26;

Authors: Majoros WH, Lekprasert P, Mukherjee N, Skalsky RL, Corcoran DL, Cullen BR, Ohler U

Abstract
High-throughput sequencing has opened numerous possibilities for the identification of regulatory RNA-binding events. Cross-linking and immunoprecipitation of Argonaute proteins can pinpoint a microRNA (miRNA) target site within tens of bases but leaves the identity of the miRNA unresolved. A flexible computational framework, microMUMMIE, integrates sequence with cross-linking features and reliably identifies the miRNA family involved in each binding event. It considerably outperforms sequence-only approaches and quantifies the prevalence of noncanonical binding modes.

PMID: 23708386 [PubMed - as supplied by publisher]

Homeostatic control of Argonaute stability by microRNA availability.

Nat Struct Mol Biol. 2013 May 26;

Authors: Smibert P, Yang JS, Azzam G, Liu JL, Lai EC

Abstract
Homeostatic mechanisms regulate the abundance of several components in small-RNA pathways. We used Drosophila and mammalian systems to demonstrate a conserved homeostatic system in which the status of miRNA biogenesis controls Argonaute protein stability. Clonal analyses of multiple mutants of core Drosophila miRNA factors revealed that stability of the miRNA effector AGO1 is dependent on miRNA biogenesis. Reciprocally, ectopic transcription of miRNAs within in vivo clones induced accumulation of AGO1, as did genetic interference with the ubiquitin-proteasome system. In mouse cells, we found that the stability of Ago2 declined in Dicer-knockout cells and was rescued by proteasome blockade or introduction of either Dicer plasmid or Dicer-independent miRNA constructs. Notably, Dicer-dependent miRNA constructs generated pre-miRNAs that bound Ago2 but did not rescue Ago2 stability. We conclude that Argonaute levels are finely tuned by cellular availability of mature miRNAs and the ubiquitin-proteasome system.

PMID: 23708604 [PubMed - as supplied by publisher]

The initiation of mRNA degradation often requires deprotection of its 5′ end. In eukaryotes, the 5′-methylguanosine (cap) structure is principally removed by the Nudix family decapping enzyme Dcp2, yielding a 5′-monophosphorylated RNA that is a substrate for 5′ exoribonucleases. In bacteria, the 5′-triphosphate group of primary transcripts is also converted...

Background: In recent years, a variety of small RNAs derived from other RNAs with well-known functions such as tRNAs and snoRNAs, have been identified. The functional relevance of these RNAs is largely unknown. To gain insight into the complexity of snoRNA processing and the functional relevance of snoRNA-derived small RNAs, we sequence long and short RNAs, small RNAs that co-precipitate with the Argonaute 2 protein and RNA fragments obtained in photoreactive nucleotide-enhanced crosslinking and immunoprecipitation (PAR-CLIP) of core snoRNA-associated proteins. Results: Analysis of these data sets reveals that many loci in the human genome reproducibly give rise to C/D box-like snoRNAs, whose expression and evolutionary conservation are typically less pronounced relative to the snoRNAs that are currently cataloged. We further find that virtually all C/D box snoRNAs are specifically processed inside the regions of terminal complementarity, retaining in the mature form only 4-5 nucleotides upstream of the C box and 2-5 nucleotides downstream of the D box. Sequencing of the total and Argonaute 2-associated populations of small RNAs reveals that despite their cellular abundance, C/D box-derived small RNAs are not efficiently incorporated into the Ago2 protein. Conclusions: We conclude that the human genome encodes a large number of snoRNAs that are processed along the canonical pathway and expressed at relatively low levels. Generation of snoRNA-derived processing products with alternative, particularly miRNA-like, functions appears to be uncommon.

Background: Previous studies in Drosophila and mammals have revealed levels of long non-coding RNAs (lncRNAs) sequence conservation that are intermediate between neutrally evolving and protein-coding sequence. These analyses compared conservation between species that diverged up to 75million years ago. However, analysis of sequence polymorphisms within a species' population can provide an understanding of essentially contemporaneous selective constraints that are acting on lncRNAs and can quantify the deleterious effect of mutations occurring within these loci. Results: We took advantage of polymorphisms derived from the genome sequences of 163 Drosophila melanogaster strains and 174 human individuals to calculate the distribution of fitness effects of single nucleotide polymorphisms occurring within intergenic lncRNAs and compared this to distributions for SNPs present within putatively neutral or protein-coding sequences. Our observations show that in D.melanogaster there is a significant excess of rare frequencyvariants within intergenic lncRNAs relative to neutrally evolving sequences, whereas selection on human intergenic lncRNAs appears to be effectively neutral. Approximately 30% of mutations within these fruitfly lncRNAs are estimated as being weakly deleterious. Conclusions: These contrasting results can be attributed to the large difference in effective population sizes between the two species. Our results suggest that while the sequences of lncRNAs will be well conserved across insect species, such loci in mammals will accumulate greater proportions of deleterious changes through genetic drift.

Genome-wide techniques provide robust and comprehensive identification of lncRNAs in adult mouse neural stem cells and their derivatives, illuminating the functions of these underappreciated transcripts.

The miRNA profiles of samples with global miRNA decrease were analyzed using Affymetrix miRNA microarrays following the inducible genetic deletion of Dicer1. Surprisingly, up to one-third of deregulated miRNAs identified upon Dicer1 depletion were found to be up-regulated following standard robust multichip average (RMA) background correction and quantile normalization, indicative of normalization bias. These findings highlight the importance of miRNA microarray normalization for the detection of miRNAs that are truly differentially expressed.

We report the imminent completion of a set of reference genome assemblies for 16 species of Anopheles mosquitoes. In addition to providing a generally useful resource for comparative genomic analyses, these genome sequences will greatly facilitate exploration of the capacity exhibited by some Anopheline mosquito species to serve as vectors for malaria parasites. A community analysis project will commence soon to perform a thorough comparative genomic investigation of these newly sequenced genomes. Completion of this project using short next generation sequence reads required innovation in both the bioinformatic and laboratory realms, and the resulting knowledge gained could prove useful for genome sequencing projects targeting other unconventional genomes.

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A novel fluorescent reporter system for monitoring and identifying RNase III activity and its target RNAs.

RNA Biol. 2012 Sep;9(9):1167-76

Authors: Kim KS, Kim KS, Park S, Lee S, Kang SB, Lee J, Lee SG, Ryu CM

Abstract
Bacteriophage vectors for achieving single-copy gene expression linked to a colorigenic reporter assay have been used successfully for genetic screening applications. However, the limited number of cloning sites in these vectors, combined with the requirement for lac- strains and the time- and/or media-dependence of the chemical-based colorimetric reaction, have limited the range of applications for these vectors. An alternative approach using a fluorescent reporter gene such as green fluorescent protein (GFP) or GFP derivatives could overcome some of these technical issues and facilitate real-time monitoring of promoter and/or protein activity. Here, we report the development of a novel translational bacteriophage fusion vector encoding enhanced GFP (eGFP) that can be incorporated into the chromosome as a single-copy gene. We identified a Bacillus promoter (BP) that is stably expressed in Escherichia coli and drives ~6-fold more expression of eGFP than the T7 promoter in the absence of inducer. Incorporating this BP and RNase III target signals into a single system enabled clear detection of the absence or downregulation of RNase III activity in vivo, thereby establishing a system for screening and identifying novel RNase III targets in a matter of days. An RNase III target signal identified in this manner was confirmed by post-transcriptional analysis. We anticipate that this novel translational fusion vector will be used extensively to study activity of both interesting RNases and related complex or to identify or validate targets of RNases that are otherwise difficult to study due to their sensitivity to environmental stresses and/or autoregulatory processes.

PMID: 22951591 [PubMed - indexed for MEDLINE]

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Ribosome profiling reveals resemblance between long non-coding RNAs and 5' leaders of coding RNAs.

Development. 2013 May 22;

Authors: Chew GL, Pauli A, Rinn JL, Regev A, Schier AF, Valen E

Abstract
Large-scale genomics and computational approaches have identified thousands of putative long non-coding RNAs (lncRNAs). It has been controversial, however, as to what fraction of these RNAs is truly non-coding. Here, we combine ribosome profiling with a machine-learning approach to validate lncRNAs during zebrafish development in a high throughput manner. We find that dozens of proposed lncRNAs are protein-coding contaminants and that many lncRNAs have ribosome profiles that resemble the 5' leaders of coding RNAs. Analysis of ribosome profiling data from embryonic stem cells reveals similar properties for mammalian lncRNAs. These results clarify the annotation of developmental lncRNAs and suggest a potential role for translation in lncRNA regulation. In addition, our computational pipeline and ribosome profiling data provide a powerful resource for the identification of translated open reading frames during zebrafish development.

PMID: 23698349 [PubMed - as supplied by publisher]

Mounia Lagha, Jacques P. Bothma, Emilia Esposito, Samuel Ng, Laura Stefanik, Chiahao Tsui, Jeffrey Johnston, Kai Chen, David S. Gilmour, Julia Zeitlinger, Michael S. Levine. Paused RNA polymerase (Pol II) is a pervasive feature of Drosophila embryos and mammalian stem cells, but its role in development is uncertain. Here, we demonstrate that a spectrum of pause....

Gal Haimovich, Daniel A. Medina, Sebastien Z. Causse, Manuel Garber, Gonzalo Millán-Zambrano, Oren Barkai, Sebastián Chávez, José E. Pérez-Ortín, Xavier Darzacq, Mordechai Choder. Maintaining proper mRNA levels is a key aspect in the regulation of gene expression. The balance between mRNA synthesis and decay determines these levels. We demonstrate that most yeast mRNAs are ....

Abundant but mysterious molecules called long noncoding RNAs have long puzzled scientists, but some now think they could be influencing the shape of chromatin.

Author: Elizabeth Pennisi

This paper describes unusual properties of group II intron-encoded reverse transcriptases. They have higher processivity, fidelity, and thermostability than retroviral enzymes. Moreover, they have an unexpected proclivity for template switching that makes them very useful for a number of cloning applications.

This paper reports results on studies of mRNA decay in Trypanosoma brucei. Surprisingly, mRNA decay of unstable and intermediate stability mRNAs is mediated by different degradative pathways.

Nature Reviews Molecular Cell Biology 14, 328 (2013). doi:10.1038/nrm3595

Author: Rachel David

The pluripotency factor LIN28 maintains stem cells in an undifferentiated state by blocking the expression of let-7 microRNAs (miRNAs). LIN28 achieves this by recruiting 3′ terminal uridylyl transferases, which add a terminal oligouridine tail to pre-let-7 that inhibits its processing and promotes miRNA decay. This

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Site-selective azide incorporation into endogenous RNase A via a "chemistry" approach.

Org Biomol Chem. 2013 Jan 14;11(2):353-61

Authors: Chen X, Henschke L, Wu Q, Muthoosamy K, Neumann B, Weil T

Abstract
Site-selective labeling of endogenous proteins represents a major challenge in chemical biology, mainly due to the absence of unique reactive groups that can be addressed selectively. Recently, we have shown that surface-exposed lysine residues of two endogenous proteins and a peptide exhibit subtle changes in their individual reactivities. This feature allows the modification of a single residue in a highly site-selective fashion if kinetically controlled labeling conditions are applied. In order to broaden the scope of the "kinetically-controlled protein labeling" (KPL) approach and highlight additional applications, the water-soluble bioorthogonal reagent, biotin-TEO-azido-NHS (11), is developed which enables the site-selective introduction of an azido group onto endogenous proteins/peptides. This bioconjugation reagent features a biotin tag for affinity purification, an azido group for bioorthogonal labeling, a TEO (tetraethylene oxide) linker acting as a spacer and to impart water solubility and an N-hydroxysuccinimidyl (NHS) ester group for reacting with the exposed lysine residue. As a proof of concept, the native protein ribonuclease A (RNase A) bearing ten available lysine residues at the surface is furnished with a single azido group at Lys 1 in a highly site-selective fashion yielding azido-(K1)RNase A. The K1 site-selectivity is demonstrated by the combined application and interpretation of high resolution MALDI-ToF mass spectroscopy, tandem mass spectroscopy and extracted ion chromatography (XIC). Finally, the water soluble azide-reactive phosphine probe, rho-TEO-phosphine (21) (rho: rhodamine), has been designed and applied to attach a chromophore to azido-(K1)RNase A via Staudinger ligation at physiological pH indicating that the introduced azido group is accessible and could be addressed by other established azide-reactive bioorthogonal reaction schemes.

PMID: 23172365 [PubMed - indexed for MEDLINE]

Ribosome profiling: a Hi-Def monitor for protein synthesis at the genome-wide scale.

Wiley Interdiscip Rev RNA. 2013 May 20;

Authors: Michel AM, Baranov PV

Abstract
Ribosome profiling or ribo-seq is a new technique that provides genome-wide information on protein synthesis (GWIPS) in vivo. It is based on the deep sequencing of ribosome protected mRNA fragments allowing the measurement of ribosome density along all RNA molecules present in the cell. At the same time, the high resolution of this technique allows detailed analysis of ribosome density on individual RNAs. Since its invention, the ribosome profiling technique has been utilized in a range of studies in both prokaryotic and eukaryotic organisms. Several studies have adapted and refined the original ribosome profiling protocol for studying specific aspects of translation. Ribosome profiling of initiating ribosomes has been used to map sites of translation initiation. These studies revealed the surprisingly complex organization of translation initiation sites in eukaryotes. Multiple initiation sites are responsible for the generation of N-terminally extended and truncated isoforms of known proteins as well as for the translation of numerous open reading frames (ORFs), upstream of protein coding ORFs. Ribosome profiling of elongating ribosomes has been used for measuring differential gene expression at the level of translation, the identification of novel protein coding genes and ribosome pausing. It has also provided data for developing quantitative models of translation. Although only a dozen or so ribosome profiling datasets have been published so far, they have already dramatically changed our understanding of translational control and have led to new hypotheses regarding the origin of protein coding genes. WIREs RNA 2013. doi: 10.1002/wrna.1172 For further resources related to this article, please visit the WIREs website.

PMID: 23696005 [PubMed - as supplied by publisher]

Structural and molecular interrogation of intact biological systems

Nature 497, 7449 (2013). doi:10.1038/nature12107

Authors: Kwanghun Chung, Jenelle Wallace, Sung-Yon Kim, Sandhiya Kalyanasundaram, Aaron S. Andalman, Thomas J. Davidson, Julie J. Mirzabekov, Kelly A. Zalocusky, Joanna Mattis, Aleksandra K. Denisin, Sally Pak, Hannah Bernstein, Charu Ramakrishnan, Logan Grosenick, Viviana Gradinaru & Karl Deisseroth

Obtaining high-resolution information from a complex system, while maintaining the global perspective needed to understand system function, represents a key challenge in biology. Here we address this challenge with a method (termed CLARITY) for the transformation of intact tissue into a nanoporous hydrogel-hybridized form (crosslinked

Phosphorylation of a microRNA-processing protein by the EGF receptor inhibits maturation of tumor-suppressing microRNAs.

cWords - systematic microRNA regulatory motif discovery from mRNA expression data.

Silence. 2013 May 20;4(1):2

Authors: Rasmussen SH, Jacobsen A, Krogh A

Abstract
BACKGROUND: Post-transcriptional regulation of gene expression by small RNAs and RNA binding proteins is of fundamental importance in development of complex organisms, and dysregulation of regulatory RNAs can influence onset, progression and potential treatment of many diseases. Post-transcriptional regulation by small RNAs is mediated through partial complementary binding to messenger RNAs leaving nucleotide signatures or motifs throughout the entire transcriptome. Computational methods for discovery and analysis of sequence motifs in high-throughput mRNA expression profiling experiments are becoming increasingly important tools for the identification of post-transcriptional regulatory motifs and the inference of the regulators and their targets. RESULTS: cWords is a method designed for regulatory motif discovery in differential case--control mRNA expression datasets. We have improved the algorithms and statistical methods of cWords, resulting in at least a factor 100 speed gain over the previous implementation. On a benchmark dataset of 19 microRNA (miRNA) perturbation experiments cWords showed equal or better performance than two comparable methods, miReduce and Sylamer. We have developed rigorous motif clustering and visualization that accompany the cWords analysis for more intuitive and effective data interpretation. To demonstrate the versatility of cWords we show that it can also be used for identification of potential siRNA off-target binding. Moreover, cWords analysis of an experiment profiling mRNAs bound by Argonaute ribonucleoprotein particles discovered endogenous miRNA binding motifs. CONCLUSIONS: cWords is an unbiased, flexible and easy-to-use tool designed for regulatory motif discovery in differential case--control mRNA expression datasets. cWords is based on rigorous statistical methods that demonstrate comparable or better performance than other existing methods. Rich visualization of results promotes intuitive and efficient interpretation of data. cWords is available as a stand-alone Open Source program at Github https://github.com/simras/cWords and as a web-service at: http://servers.binf.ku.dk/cwords/.

PMID: 23688306 [PubMed - as supplied by publisher]

Nature advance online publication 19 May 2013. doi:10.1038/nature12172

Authors: Alex K. Shalek, Rahul Satija, Xian Adiconis, Rona S. Gertner, Jellert T. Gaublomme, Raktima Raychowdhury, Schragi Schwartz, Nir Yosef, Christine Malboeuf, Diana Lu, John T. Trombetta, Dave Gennert, Andreas Gnirke, Alon Goren, Nir Hacohen, Joshua Z. Levin, Hongkun Park & Aviv Regev

Recent molecular studies have shown that, even when derived from a seemingly homogenous population, individual cells can exhibit substantial differences in gene expression, protein levels and phenotypic output, with important functional consequences. Existing studies of cellular heterogeneity, however, have typically measured only a few pre-selected RNAs or proteins simultaneously, because genomic profiling methods could not be applied to single cells until very recently. Here we use single-cell RNA sequencing to investigate heterogeneity in the response of mouse bone-marrow-derived dendritic cells (BMDCs) to lipopolysaccharide. We find extensive, and previously unobserved, bimodal variation in messenger RNA abundance and splicing patterns, which we validate by RNA-fluorescence in situ hybridization for select transcripts. In particular, hundreds of key immune genes are bimodally expressed across cells, surprisingly even for genes that are very highly expressed at the population average. Moreover, splicing patterns demonstrate previously unobserved levels of heterogeneity between cells. Some of the observed bimodality can be attributed to closely related, yet distinct, known maturity states of BMDCs; other portions reflect differences in the usage of key regulatory circuits. For example, we identify a module of 137 highly variable, yet co-regulated, antiviral response genes. Using cells from knockout mice, we show that variability in this module may be propagated through an interferon feedback circuit, involving the transcriptional regulators Stat2 and Irf7. Our study demonstrates the power and promise of single-cell genomics in uncovering functional diversity between cells and in deciphering cell states and circuits.

miRNAs are small RNA molecules ('22 nt) that interact with their target mRNAs inhibiting translation or/and cleavaging the target mRNA. This interaction is guided by sequence complentarity and results in the reduction of mRNA and/or protein levels. miRNAs are involved in key biological processes and different diseases. Therefore, deciphering miRNA targets is crucial for diagnostics and therapeutics. However, miRNA regulatory mechanisms are complex and there is still no high-throughput and low-cost miRNA target screening technique. In recent years, several computational methods based on sequence complementarity of the miRNA and the mRNAs have been developed. However, the predicted interactions using these computational methods are inconsistent and the expected false positive rates are still large. Recently, it has been proposed to use the expression values of miRNAs and mRNAs (and/or proteins) to refine the results of sequence-based putative targets for a particular experiment. These methods have shown to be effective identifying the most prominent interactions from the databases of putative targets. Here, we review these methods that combine both expression and sequence-based putative targets to predict miRNA targets.

Potential role of human-specific genes, human-specific microRNAs and human-specific non-coding regulatory RNAs in the pathogenesis of Systemic Sclerosis and Sjögren's Syndrome.

Autoimmun Rev. 2013 May 15;

Authors: Jimenez SA, Piera-Velazquez S

Abstract
The etiology and pathogenesis of human autoimmune diseases remain unknown despite intensive investigations. Although remarkable progress has been accomplished through genome wide association studies in the identification of genetic factors that may predispose to their occurrence or modify their clinical presentation to date no specific gene abnormalities have been conclusively demonstrated to be responsible for these diseases. The completion of the human and chimpanzee genome sequencing has opened up novel opportunities to examine the possible contribution of human specific genes and other regulatory elements unique to the human genome, such as microRNAs and non-coding RNAs, towards the pathogenesis of a variety of human disorders. Thus, it is likely that these human specific genes and non-coding regulatory elements may be involved in the development or the pathogenesis of various disorders that do not occur in non-human primates including certain autoimmune diseases such as Systemic Sclerosis and Primary Sjögren's Syndrome. Here, we discuss recent evidence supporting the notion that human specific genes or human specific microRNA and other non-coding RNA regulatory elements unique to the human genome may participate in the development or in the pathogenesis of Systemic Sclerosis and Primary Sjögren's Syndrome.

PMID: 23684698 [PubMed - as supplied by publisher]