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Cited by 968MicroRNA in disease regulationGene expression and cancer classificationPlant Molecular Biology Research

Distribution of miRNA expression across human tissues

Open access
Ludwig, Nicole, Leidinger, Petra, Becker, Kurt, Backes, Christina, Fehlmann, Tobias, Pallasch, Christian, Rheinheimer, Steffi, Meder, Benjamin +3 more·2016·Nucleic Acids Research
DOI 10.1093/nar/gkw116PMC PMC4856985
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Abstract

We present a human miRNA tissue atlas by determining the abundance of 1997 miRNAs in 61 tissue biopsies of different organs from two individuals collected post-mortem. One thousand three hundred sixty-four miRNAs were discovered in at least one tissue, 143 were present in each tissue. To define the distribution of miRNAs, we utilized a tissue specificity index (TSI). The majority of miRNAs (82.9%) fell in a middle TSI range i.e. were neither specific for single tissues (TSI > 0.85) nor housekeeping miRNAs (TSI < 0.5). Nonetheless, we observed many different miRNAs and miRNA families that were predominantly expressed in certain tissues. Clustering of miRNA abundances revealed that tissues like several areas of the brain clustered together. Considering -3p and -5p mature forms we observed miR-150 with different tissue specificity. Analysis of additional lung and prostate biopsies indicated that inter-organism variability was significantly lower than inter-organ variability. Tissue-specific differences between the miRNA patterns appeared not to be significantly altered by storage as shown for heart and lung tissue. MiRNAs TSI values of human tissues were significantly (P = 10(-8)) correlated with those of rats; miRNAs that were highly abundant in certain human tissues were likewise abundant in according rat tissues. We implemented a web-based repository enabling scientists to access and browse the data (https://ccb-web.cs.uni-saarland.de/tissueatlas).

AI snapshot

Written from the paper’s full text.

TL;DR

This paper presents a human miRNA tissue atlas by profiling 1,997 mature miRNAs across 61 post-mortem tissue biopsies from two male individuals, with 1,364 miRNAs detected in at least one tissue and 143 detected in all tissues. It reports tissue-specific miRNA patterns, a web repository, and conserved tissue specificity between human and rat.

Key findings

  • Of 1,997 mature miRNAs, 633 (31.7%) were not detected in any tested tissue; 1,364 were detected in at least one tissue, and 143 (10.5%) were found in all tissues.
  • Most detected miRNAs had intermediate tissue specificity: 82.9% fell in a middle TSI range, neither tissue-specific (TSI > 0.85) nor housekeeping (TSI < 0.5); in quantile-normalized data, 83.7% of miRNAs in the first body and 88.8% in the second body had intermediate TSI values.
  • Tissue-specific examples included miR-1–3p as the overall most tissue-specific miRNA, high in muscle and myocardium; miR-122–5p in liver, miR-7–5p in pituitary gland, miR-205–5p in skin, and miR-507/miR-514a-3p/miR-509–5p in testis.
  • Human and rat tissue specificity was significantly correlated (TSI correlation 0.362, P = 9 × 10−8; permutation average correlation 0), and inter-individual variability was significantly lower than inter-organ variability in lung and prostate analyses (P < 10−16).

Methods

  • Profiled 61 tissue biopsies from two male cadavers (65-year-old with multiple myeloma; 59-year-old with no signs of cancer) using Agilent SurePrint 8 × 60K Human V19 miRNA microarrays, covering 1,997 human miRNAs present in both miRBase V19 and V21.
  • Pre-analytics included 44 tissue miRNomes for reproducibility and storage/degradation analyses, 16 additional normal lung biopsies from different individuals, and GEO datasets from normal gastric and prostate tissues.
  • Calculated a tissue specificity index (TSI) for each miRNA, performed hierarchical clustering, miRNA family and co-expression analyses, and compared human TSI values with rat data from GEO series GSE52754; analyses used raw, quantile-normalized, and variance-stabilized normalized data.

Limitations

  • The paper states that autopsy samples from only two male individuals provide only a snapshot of full miRNA expression variability, and that age, sex, and disease status can influence miRNA patterns.
  • The authors state they cannot exclude that some tissue-specific miRNAs might be affected by sample degradation, although storage between 1 and 14 days at 4°C had limited overall impact on tissue miRNA patterns.
  • The paper notes that microarray analysis cannot detect presently unknown miRNAs or miRNA isoforms, and that normalization choice can substantially influence results; these are stated limitations of the platform and analysis approach.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1093/nar/gkw116

Cites

29 of 29 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 34 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The overall most tissue-specific miRNA was miR-1-3p.

    “The overall most tissue-specific miR-1–3p is presented in Figure 3.”
    Quote in the paperNot a substantial claim
  • Findingown data

    There is no significant difference in TSI values between -3p and -5p mature forms (P > 0.5 for both VSN- and quantile-normalized data).

    “For both, TSI values based on VSN- and quantile-normalized data, we did not found significant differences between -3p and -5p forms (P > 0.5 in both cases).”
    Quote in the paperSubstantial claim
  • Findingown data

    Co-expression is frequently observed among mature members of specific miRNA families (e.g., mir-548).

    “While we frequently observed co-expression among mature members of specific families (e.g. the mir-548 family)”
    Quote in the paperNot a substantial claim
  • Findingown data

    miR-507, miR-514a-3p and miR-509-5p were almost exclusively expressed in the testis samples.

    “Another group of miRNAs, miR-507, miR-514a-3p and miR-509–5p was almost exclusively expressed in the testis samples.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Five miRNAs had TSI values increased in lung tissue by at least 20%: hsa-miR-8069, hsa-miR-6821-5p, hsa-miR-4800-5p, hsa-miR-6775-5p, hsa-miR-5001-5p.

    “Especially for five miRNAs we, however, calculated TSI values that are increased in lung tissue by at least 20%: hsa-miR-8069, hsa-miR-6821–5p, hsa-miR-4800–5p, hsa-miR-6775–5p, hsa-miR-5001–5p.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 35
  • The quote only partly states this claim. 4
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Findingown data

    Specific miRNAs in the heat map matched known specific miRNAs, such as miR-133a-3p and miR-133b for muscle and myocardium, or miR-9-5p, miR-219a-5p, miR-7-5p and miR-124-3p for brain and spinal cord.

    “The miRNAs in this heat map matched the specific miRNAs in Figure 5 very well such as miR-133a-3p, and miR-133b for muscle and myocardium or miR-9–5p, miR-219a-5p, miR-7–5p and miR-124–3p for brain and spinal cord.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Highly specific expression of miR-205-5p, miR-514a-3p and miR-192-5p was detected in skin, testis and colon samples of one of the bodies, respectively.

    “Additionally, we detected a highly specific expression of miR-205–5p, miR-514a-3p and miR-192–5p in skin, testis and colon samples of one of the bodies, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of 10 replicated Agilent microarray measurements of the same individual, minimal correlation was 0.998 and mean/median correlation 0.999.

    “Of 10 replicated Agilent microarray measurements of the same individual, we calculated 10 * 9/2 pair-wise correlations of technical replicates. Minimal correlation was 0.998 and mean/median correlation 0.999, highlighting the high degree of technical reproducibility of the array platform.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Their results correlated well with Landgraf data, confirming specific expression of miR-122, miR-9, miR-124 and miR-7 in the respective organs.

    “Overall, our results correlated well with this data, confirming specific expression of miR-122, miR-9, miR-124 and miR-7 in the respective organs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Analysis with raw data detected an increased number of co-expressions but generally confirmed the observation based on normalized data.

    “Performing the same analysis with raw data, we detected an increased number of co-expressions, but generally confirmed the observation that has been based on the normalized data.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The overall correlation of expression values of rat and human miRNAs was 0.361 (P < 10−16), indicative of significant matching of human and rat expression profiles.

    “However, the overall correlation of the expression values of rat and human miRNAs was 0.361 (P < 10−16), indicative of a significant matching of human and rat expression profiles.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    For miRNAs with two mature forms, -5p forms are on average 21% higher expressed than -3p forms (paired t-test P=3.6×10−10), for both quantile- and VSN-normalized data.

    “Mature -5p forms were on average 21% higher expressed as compared to -3p forms (paired t-test P-value of 3.6×10−10).”
    • Also stated in: § Tissue specificity of -3p and -5p mature forms · plain
      “For both quantile- and VSN-normalized data, we calculated significantly higher expression of the -5p mature forms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The miR-378 family has the highest tissue specificity, predominantly specific for myocardium and muscle.

    “Highest tissue specificity was observed for the miR-378 family, predominantly being specific for myocardium and muscle.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-449a is expressed in lung, kidney and brain.

    “miR-449a in lung, kidney and brain”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    High correlations between technical replicates were found, with overall lowest correlations at 0.986 and 0.994 for liver and pleura, and highest correlation 0.999 for brain samples.

    “Altogether, we found high correlations between these technical replicates with the overall lowest correlations at 0.986 and 0.994 observed for liver tissue and pleura, respectively. Highest correlation of 0.999 was reached for the brain samples.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Several miRNA families have high TSI values, including the mir-378 family whose members show high abundance in muscle tissues and myocardium.

    “We found several miRNA families with high TSI values including the above-mentioned mir-378 family with most of the family members showing a high abundance in muscle tissues and the myocardium.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    These differentially abundant miRNAs had low TSI values and are not considered tissue specific.

    “Although these (and similarly differentially abundant miRNAs between both individuals) miRNAs had low TSI values and are not considered tissue specific”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    miR-124 is expressed in different areas of the brain but not in other tissues.

    “We observed expression of this miRNA in different areas of the brain but not in other tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    miR-144 has highest expression in vein and spleen, and high expression in thyroid.

    “For miR-144, we found highest expression in vein and spleen, consistent with the assumption of residual hematopoietic cells in these samples; additionally, we found high expression of this miRNA in thyroid.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    miRNAs with higher TSI in lung were usually specific for other organs and expressed to a very moderate limit in the lung; small variations lead to artificially high TSI values.

    “Inspecting the respective miRNAs, we found that they usually were specific for other organs than the lung and expressed to a very moderate limit in the lung. Here, already small variations lead to artificially high TSI values.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For VSN-normalized data, a similar clustering pattern was observed, but with a stronger tendency of clustering of individuals in different sub-clusters.

    “For VSN-normalized data we observed a similar pattern, however, we found a stronger tendency of clustering of individuals in the different sub-clusters”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Restricting clustering to the 100 miRNAs with highest data variance found a first main cluster containing kidney, liver, stomach and small intestine of both bodies.

    “Here, we found three main clusters with the first one containing kidney, liver, stomach and small intestine of both bodies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Few miRNAs have higher TSI in lung compared to the overall TSI, i.e., variations between organs are smaller than variations between individuals.

    “These figures also indicate that few miRNAs have higher TSI in lung as compared to the overall TSI, i.e. variations between organs are smaller than variations between individuals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    230 miRNAs matched in sequence identically between human and rat; 42 organs could be matched between the human and rat studies.

    “From all miRNAs expressed in our tissue collection, 230 matched in sequence identically between human and rat. Of the tissues included in the human and rat studies, 42 organs could be matched.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Hierarchical clustering of miRNAs and tissues found two major clusters; the first mainly contained nervous system tissues and muscle tissues from both bodies.

    “We found two major clusters, the first of which containing mainly nervous system tissues and muscle tissues from both bodies.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    They identified 73 miRNA pairs with tissue co-expression (Pearson correlation >0.95).

    “Altogether, we identified 73 miRNA pairs with tissue co-expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    High expression of miR-133b, miR-133a-3p, miR-1-3p and miR-206 was detected in both muscle samples and, with the exception of miR-206, also in both myocardial samples.

    “In detail, we detected high expression of miR-133b, miR-133a-3p, miR-1–3p and miR-206 in both muscle samples and, with the exception of miR-206 also in both myocardial samples.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In clustering of 54 miRNAs with TSI > 0.9, there was no predominant clustering by species but a strong tendency of organs to cluster together.

    “In this analysis we did not observe a predominant clustering in humans and rats but a strong tendency of organs to cluster together.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In 32 prostate tissues, variations between individuals were even lower than variations between organs; TSI values were significantly lower for prostate tissue (P < 10−16).

    “In this analysis the variations between individuals were even lower as compared to the variations between organs. Again, TSI values were significantly lower for prostate tissue (P < 10−16).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Clustering with the 25 miRNAs displaying TSI > 0.85 for both bodies in raw-, quantile- and VSN-normalized data found several groups of miRNAs with tissue-specific expression.

    “We found several groups of miRNAs with tissue-specific expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In lung and heart tissue, short- and long-term degradation had an overall limited impact on the tissue specificity of miRNA profiles; only very few miRNAs were affected.

    “For lung and heart tissue we investigated short- and long-term degradation, highlighting an overall limited impact on the tissue specificity of miRNA profiles. Only very few miRNAs were affected at all.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All lung and all heart samples each clustered together in hierarchical cluster analysis.

    “Hierarchical cluster analysis shows that all lung and all heart samples each cluster together (Figure 1; Supplementary Figure S1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    miR-205-5p is highly expressed in melanocytes and downregulated in melanoma, and is inversely correlated with melanoma progression (21).

    “MiR-205–5p that is highly expressed in melanocytes and downregulated in melanoma is inverse correlated with melanoma progression (21).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The authors' previous investigation of different blood cell types indicated a complex miRNA repertoire strongly dependent on cell types.

    “We recently investigated the miRNA repertoire of different blood cell types (4), already indicating a complex miRNA repertoire strongly dependent on the considered cell types.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    NGS analysis would enable detection of presently unknown miRNAs as well as miRNA isoforms that have demonstrated to target biological pathways in a cooperative manner (16).

    “However, NGS analysis would enable to detect presently unknown miRNAs as well miRNAs iso-forms that have demonstrated to target biological pathways in a cooperative manner (16).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Age and gender are known to influence the miRNA pattern (12).

    “different donors should be of different age and gender both of which are known to influence the miRNA pattern (12).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Landgraf et al. identified miR-124 (miR-124-3p) as the third most specific miRNA in the nervous system.

    “MiR-124 (miR-124–3p) was identified as the third most specific miRNA in the nervous system by Landgraf et al.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] source

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    All analyses were performed on raw data, quantile-normalized data, and variance stabilizing normalization (VSN) to account for normalization impact.

    “Since the normalization may have an impact on the results, we performed all analyses on the raw data, normalized data by quantile normalization and by variance stabilizing normalization (6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    miR-514a-3p belongs to the miR-506 family; the mouse orthologue of miR-506, mmu-201, has been shown to be specifically expressed in reproductive tissues (3).

    “MiR-514a-3p belongs to the miR-506 family; the mouse orthologue of miR-506, mmu-201, has been shown to be specifically expressed in reproductive tissues (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Landgraf et al. identified 340 mature human miRNAs including 33 novel miRNAs not listed in miRBase version 9.1.

    “They identified 340 mature human miRNAs including 33 novel miRNAs not listed in the miRBase version 9.1, which was the current version at the time of the study (17).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] source

  • May combine two claims.

    Premisecitation

    Landgraf et al. detected tissue-specific expression of miR-122 in liver, miR-9, miR-124 and miR-128a/b in brain, miR-7, miR-375, miR-141 and miR-200a in pituitary gland, and miR-142, miR-144, miR-150, miR-155 and miR-223 in hematopoietic cells.

    “Amongst others, Landgraf et al. detected tissue-specific expression of miR-122 in liver, of miR-9, miR-124 and miR 128a/b in brain, of miR-7, miR-375, miR-141 and miR-200a in pituitary gland and of miR-142, miR-144, miR-150, miR-155 and miR-223 in hematopoietic cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    miR-144 has been found highly expressed in normal thyroid and downregulated in papillary thyroid carcinoma (18).

    “Of note, miR-144 has been found highly expressed in normal thyroid and downregulated in papillary thyroid carcinoma (18).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A web-based repository was implemented to enable scientists to access and browse the data.

    “We implemented a web-based repository enabling scientists to access and browse the data (https://ccb-web.cs.uni-saarland.de/tissueatlas).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    Given data from two organs, it cannot be excluded that some tissue-specific miRNAs might be affected by degradation of the sample.

    “Given the data from two organs, we however cannot exclude the possibility that some tissue-specific miRNAs might be affected by degradation of the sample.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    The applied Agilent microarray technology has been proven sensitive and reproducible in a recent comprehensive platform comparison.

    “The applied Agilent microarray technology has been proven sensitive and, more important, reproducible in a recent comprehensive platform comparison (5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    RNA integrity values (RIN) ranged between 1.8 and 2.7 for the autopsy samples.

    “As expected for autopsy samples, the RNA integrity values (RIN) ranged between 1.8 and 2.7.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: RNA integrity values between 1.8 and 2.7 in autopsy samples are sufficient for reliable miRNA profiling.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Technical Pearson correlation coefficients between 0.97 and 1 were achieved for technical replicates in previous studies using this technology.

    “Using this technology, we achieved technical Pearson correlation coefficients of between 0.97 and 1 for technical replicates in previous studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The most comprehensive study on tissue-specific miRNAs in humans as of now was published by Landgraf et al. in 2007 (3).

    “The, as of now, most comprehensive study on tissue-specific miRNAs in humans was published by Landgraf et al. in 2007 (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    These miRNAs are known as myomiRs that regulate key genes in muscle development (19,20).

    “These miRNAs are known as myomiRs that regulate key genes in muscle development (19,20).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] source
    • cites [20] source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    RNA degradation due to prolonged inadequate tissue storage has a random effect on miRNAs and compromises the reliability of miRNA profiles, generating false positive deregulated miRNAs (15).

    “Ibberson et al. found that RNA degradation due to prolonged inadequate tissue storage has a random effect on miRNAs and compromises the reliability of miRNA profiles, generating false positive deregulated miRNAs (15).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] source

  • May combine two claims.

    Interpretationreasoning

    TSI does not acknowledge the origin of miRNAs; a value of 1 for a rat miRNA may indicate specificity for spleen and for the same miRNA specificity for brain in humans.

    “While these results indicate an overall matching of miRNA abundances in humans and rats, the TSI does not acknowledge the origin of the miRNAs, i.e. a value of 1 for a rat miRNA may indicate specificity for spleen and for the same miRNA specificity for brain in humans.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Landgraf et al. sequenced 256 small RNA libraries from 26 different organ systems and cell types of humans and rodents, with ∼1000 clones each.

    “They sequenced 256 small RNA libraries from 26 different organ systems and cell types of humans and rodents, with ∼1000 clone each.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The autopsy samples of the two male individuals provide only a snapshot of the full variability of miRNA expression.

    “We are also aware that the autopsy samples of the two male individuals provide only a snapshot of the full variability of miRNA expression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Technical replicates from nine randomly selected tissue samples from the second body always clustered together, showing the applied technology was suited to provide reproducible results.

    “Hierarchical cluster analysis shows that the technical replicates always clustered together showing that the applied technology was suited to provide reproducible results”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A significant decrease in expression of miR-192-5p in colorectal cancer compared to normal mucosa has been reported (22).

    “A significant decrease in expression of miR-192–5p in colorectal cancer compared to normal mucosa has been reported (22).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Elevated levels of circulating myomiRs (miR-1, miR-206 and miR-133a/b) have been proposed as biomarkers for heart failure and different forms of muscle dystrophy, but are also elevated after half-marathon run (27-29).

    “Elevated levels of circulating myomiRs, i.e. miR-1, miR-206 and miR-133a/b, have been proposed as biomarker for heart failure and different forms of muscle dystrophy, but are also elevated after half-marathon run (27–29).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [27] source
    • cites [28] source
    • cites [29] source
51 of 51

  • The paper relies on this without support.

    The two post-mortem male individuals are representative of the general human population for tissue miRNA distribution.

    “Tissues analysed in this study originated from two male bodies.”
    “we measured all miRNA profiles from only two different individuals to minimize inter-individual variability.”

  • The paper relies on this without support.

    The first individual's multiple myeloma did not substantially alter the miRNA profiles of his non-tumor tissues.

    “The first body was from a 65-year-old male patient, who suffered from multiple myeloma, a cancer that forms in a type of white blood cells (plasma cells).”

  • The paper relies on this without support.

    RNA integrity values between 1.8 and 2.7 in autopsy samples are sufficient for reliable miRNA profiling.

    “As expected for autopsy samples, the RNA integrity values (RIN) ranged between 1.8 and 2.7.”

  • The paper relies on this without support.

    The majority of studies investigate differential expression in only one organ/tissue.

    “Although there is ample evidence for differential miRNA expression in different human tissues, the majority of studies investigate differential expression in only one organ/tissue.”

  • The paper relies on this without support.

    Results of studies are not easily comparable due to different identification methods and normalization strategies, limiting their value for comparison of miRNA expression in different tissues.

    “Due to the different identification methods and normalization strategies, the results of these studies are not easily comparable limiting their value for comparison of miRNA expression in different tissues.”

  • The paper relies on this without support.

    Biopsies will be mostly taken from patients with affected organs.

    “biopsies will be mostly taken from patients with affected organs”

  • The paper relies on this without support.

    High inter-individual differences can mask tissue-specific differences of miRNA abundances.

    “high inter-individual differences can mask tissue-specific differences of miRNA abundances”

  • The paper relies on this without support.

    A bias is likely introduced by multiple centres involved in tissue collections.

    “a bias is likely introduced by multiple centres that are involved in tissue collections”

  • The paper relies on this without support.

    Samples of vital organs (e.g., thalamus, spinal cord, cerebellum) are not available from biopsies.

    “samples of vital organs, e.g. thalamus, spinal cord or cerebellum, are not available”

  • The paper relies on this without support.

    RNA degradation in autopsy samples due to storage duration, advanced age, or disease status of body donors.

    “with the disadvantage of RNA degradation in the samples due to the storage duration of the body and the advanced age or the disease status of the body donors”

  • The paper relies on this without support.

    Many normalization techniques can have a substantial influence on the results.

    “Many techniques that are frequently applied such as variance stabilizing normalization or quantile normalization can have a substantial influence on the results.”
11 of 11

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Many miRNAs have a strong tissue-specific expression pattern and the 3' UTR of target gene plays a critical role in determining miRNA-target interaction.

    “Many miRNAs have a strong tissue-specific expression pattern and 3’ UTR of target gene plays a critical role in determining the miRNA-target interaction [136, 137].”

    From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [136]

    The Results section ('Frequency of miRNAs per tissue and tissue specificity of miRNAs'; page unavailable) reports 222 miRNAs with highly tissue-specific expression, supporting the first part of the sentence. Our copy does not address whether a target gene’s 3′ UTR determines miRNA–target interactions, so it does not support that part. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Well-described brain-specific miRNAs include mir-9, mir-124, mir-219, mir-338, and miRNAs missing from existing catalogs include mir-666, mir-878, mir-433.

    “We identified both well-described brain-specific miRNAs, such as mir-9, mir-124, mir-219, mir-338 (16, 24, 33), as well as those which are missing from existing catalogs, such as mir-666, mir-878, mir-433, etc.”

    From A mouse tissue atlas of small noncoding RNA (2020) · cites this paper as [33]

  • These and subsequent studies have not unraveled cellular microRNA expression.

    “While providing valuable insights into the relationship of microRNA expression and disease (Lu et al. 2005), these and subsequent studies (Cheng et al. 2015; Ludwig et al. 2016) have not unraveled cellular microRNA expression.”

    From Toward the human cellular microRNAome (2017) · cites this paper as Ludwig et al. 2016

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • miR-122-5p is called exclusive to liver despite detection elsewhere

    Minor

    The results call miR-122-5p exclusively expressed in liver, whereas the discussion reports its expression in three other tissue types.

  • Human-rat TSI correlation has two stated P-values

    Minor

    The abstract gives P = 10−8, while the results give P = 9 × 10−8 for the human-rat TSI correlation.

  • The 16 additional lung biopsies are described as both normal and cancer tissue

    Minor

    The methods describe these biopsies as normal lung tissue, but the additional-data section calls them lung cancer tissues.

  • Co-expression correlations are identified as both Pearson and Spearman

    Minor

    The methods and Figure 6B identify the co-expression measure as Spearman correlation, but the results say the 0.95 cutoff was applied to Pearson correlation.

4 of 4

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Authors
Ludwig, N., Leidinger, P., Becker, K., Backes, C., Fehlmann, T., Pallasch, C., Rheinheimer, S., Meder, B., Stähler, C., Meese, E., & Keller, A.
Affiliations
  • Saarland University (DE)
  • Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
  • University Hospital Heidelberg (DE)
  • Siemens Healthineers (Germany) (DE)
Corresponding author
Keller, Andreas
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2016-02-25
Volume
44
Issue
8
Pages
3865-3877
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gkw116
PMC
PMC4856985
OpenAlex
W2288482887
Semantic Scholar
dc9823564677f04a2e1f18bb6ed9f2c7fef80a0e
Cited by
968
References
29
Citations by year
2026: 45 · 2025: 73 · 2024: 93 · 2023: 97 · 2022: 104 · 2021: 138 · 2020: 141 · 2019: 109 · 2018: 88 · 2017: 61 · 2016: 17 · 2015: 1
FWCI
32.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
Universität des Saarlandes
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Molecular Biology Research
Keywords
microRNA expression, human tissue atlas, miRNA abundance, miR-150, brain, lung, prostate, heart, rat comparison, postmortem tissue, web-based repository
MeSH terms
Adult, Aged, Animals, Humans, Male, Organ Specificity, Tissue Distribution, Reproducibility of Results, Databases, Nucleic Acid, MicroRNAs, Rats

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-06.

Statistics and arithmetic are recomputed, not judged.

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