LncRNA GO annotation manual

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LncRNAs have multiple and varied activities (see [PMID:31048766]. Some example annotations are given below.

miRNA inhibitor activity

Some lncRNAs have been shown to able to bind miRNAs and prevent them from inhibiting the expression of mRNAs. These lncRNAs are somethings referred to as miRNA sponges, decoys or competing endogenous RNAs. A decision tree is provided below to assist annotation.

Decision tree to assist with curation of lncRNA:miRNA interactions

These guidelines are for the curation of lncRNAs that bind to miRNA and prevent miRNA activity. These lncRNAs are may be described as miRNA sponges, decoys or competing endogenous RNAs. In these instances, the lncRNA may be destroyed as part of the process. As such, there needs to be a large excess of lncRNA over the miRNA target to be effective. Target-directed microRNA degradation is a distinct process where the lncRNA is not consummed and so the lncRNA does not need to be in massive excess over the miRNA target.

Link to LncRNA_Decision_Tree pdf[[1]]

Decision Tree for the GO terms and annotation extensions used for capturing targets of lncRNAs. The types of evidence in the blue boxes are described further in the text. Information about the cell or tissue that the interaction occurs in can be captured for example in the annotation extension field using: occurs_in (insert cell ontology ID and/or UBERON ID based on cell and/or tissue type respectively). This information can be included when inhibition of the lncRNA leads to an increase in the endogenous miRNA (or decrease in the miRNA target protein level). Slightly weaker evidence to support inclusion of the cell or tissue information would be evidence that the lncRNA is expressed in these cells/this tissue AND that the authors are confident that the lncRNA target is also being regulated in these cells/this tissue. For example, when the addition of the lncRNA leads to a decrease in the endogenous miRNA or increase in the endogenous protein level.

Note: to be able to indicate any target in a GO annotation, the prediction evidence does not need to be in the paper you are annotating, it could be from another paper or a prediction database. When looking at predictions or validations in a prediction database, it is recommended to check the references cited for the target as they may serve as a good source of experimental annotation. Additionally, it has been found that some of the cited papers do not support the validation of the targets. Annotations to “miRNA inhibitor activity via base pairing” (GO:0140869) should ONLY be made from the paper containing the experimental evidence, however it is acceptable to indicate in the annotation extension of a “gene silencing by miRNA” annotation that the target of gene silencing is direct (by using has_input) if the evidence for binding is in another paper.

Annotation example:[A Network of Noncoding Regulatory RNAs Acts in the Mammalian Brain]. Description:Cyrano, harbouring miR-7 binding site and mediates its destruction by target-RNA-directed miRNA degradation.

LncRNA Oip5os1 (Cyrano) annotations (mouse, URS000075A502_10090, URS000075B8A8_10090) [PMID:29887379].

  • MF GO:0140869 miRNA inhibitor activity via base-pairing
    • has_input URS0000591950_10090 (miR-7b-5p)& URS000075DE8D_10090 (miR-7a-5p)
  • BP: GO:0000512 lncRNA-mediated post-transcriptional gene silencing
  • BP: GO:0140958 target-directed miRNA degradation

Note that the level of Oip5os1 does not change but the level of target miR-7 is down-regulated dramatically, as the lncRNA is not destroyed in the process. If the lncRNA decreases with the miRNA, then it is not target-directed miRNA degradation, but can be annotated with another more appropriate term such as GO:0010587 miRNA catabolic process.

mRNA translation repression

Annotation Example:[LincRNA-p21 suppresses target mRNA translation.] Description: In the absence of HuR, lincRNA-p21 binds mRNA targets to repress their translation by recruiting the translation repressor Elavl1 (Rck).

LncRNA (mouse lincRNA-p21 URS00002D0335_10090) annotations based on [PMID:22841487]:

  • MF: GO:1903231 mRNA base-pairing translational repressor activity
    • has_input UniProt:Q02248|UniProt:P16858|UniProt:P09450
  • MF: GO:0160134 protein-RNA sequence-specific adaptor activity
    • has_input UniProt:P70372
  • BP: GO:0000512 lncRNA-mediated post-transcriptional gene silencing

Chromatin adaptor

Annotation Example 1:[The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3]. Description: Mouse Xist lncRNA interacts with Spen, hnRNPU and LBR and mediate X-chromsome silencing in dosage compensation.

LncRNA (mouse Xist URS000077A8CE_10090) annotations based on [PMID:25915022]:

  • MF: GO:0140463 chromatin-protein adaptor activity
    • has_input UniProtKB:Q62504, UniProtKB:Q62504Q8VEK3, UniProtKB:Q3U9G9
  • BF: GO:0060816 random inactivation of X chromosome

Annotation Example 2:[Topological organization of multichromosomal regions by the long intergenic noncoding RNA Firre.]: Description: Firre transcripts localize to their transcription site and five additional autosomal chromosomal loci in trans to affect interactions between distant genomic regions.

LncRNA (Human Firre (URS00002F3F76_9606) annotations based on [PMID:24463464]

  • MF: GO:0140463 chromatin-protein adaptor activity
  • BP: GO:0006325 chromatin organization

Protein sequestering

Annotation Example: [A long noncoding RNA protects the heart from pathological hypertrophy]. Description: LncRNA Mhrt sequesters Smarca4 (Brg1) from its genomic DNA targets to prevent chromatin remodelling.

LncRNA (Mouse Mhrt URS00007E4CE3_9606) annotations based on [PMID:25119045]:

  • MF: GO:0140311 protein sequestering activity
    • has_input UniProt:Q3TKT4
  • BP: GO:0006338 chromatin remodeling

Triplex-Mediated Changes in Chromatin Structure

Annotation example: [LncRNA Khps1 Regulates Expression of the Proto-oncogene SPHK1 via Triplex-Mediated Changes in Chromatin Structure ]. Description: Khps1 binds to the Sphk1 promoter via a DNA-RNA triplex and recruits the histone acetyltransferase Ep300 (p300/CBP) leading to changes of the chromatin structure to enhance E2F1 binding to promote the transcription of Sphk1.

LncRNA (Rat Khps1 RNAcentral:URS00008E3A43_10116) annotations based on [PMID:26590717]:

  • MF: GO:0141180 dsDNA-RNA triple helix-forming chromatin adaptor activity
    • has_input UniProt:Q5RJS0, ENSEMBL:ENSRNOG00000010626
  • BP: GO:0006325 chromatin organization
  • BP: GO:0045944 positive regulation of transcription by RNA polymerase II

Transcription coregulator activity

Annotation example: [Drosophila Relish Activating lncRNA-CR33942 Transcription Facilitates Antimicrobial Peptide Expression in Imd Innate Immune Response]. LncRNA:CR33942 interacts and enhances the binding of NF-κB transcription factor Relish to Dpt and AttA promoters and enhances their transcription as part of the peptidoglycan recognition protein (IMD) signaling pathway.

LncRNA (Drosophila lncRNA:CR33942 RNAcentral:URS0000809E6D_7227) annotations based on [PMID:35720331]:

  • MF: GO:0003713 transcription coactivator activity
    • has_input FB:FBgn0014018 (Rel)
  • BP: GO:0045944 positive regulation of transcription by RNA polymerase II
  • BP: GO:0061059 positive regulation of peptidoglycan recognition protein signaling pathway

Phase separation

Annotation Example: [Altered nuclear retention of mRNAs containing inverted repeats in human embryonic stem cells: functional role of a nuclear noncoding RNA]. Description: NEAT1 is an architectural lncRNA that nucleates paraspeckles.

LncRNA (human NEAT1 URS0000204428_9606) annotations based on [PMID:19716791]:

  • MF: GO:0140693 molecular condensate scaffold activity
  • BP: GO:0030575 nuclear body organization

Regulation of post-translational modifications

Annotation Example: [The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation]. Description: Lnc-DC (HSALNT0243356) directly interacts with STAT3 to prevent its dephosphorylation by SHP1 (PTPN6).

LncRNA annotations URS00007B42BD_9606/URS00007B3652_9606 (human HSALNT0243356 GenBank:KJ020271 and GenBank:KJ020272) from [PMID:24744378].

  • MF: GO:0019212 phosphatase inhibitor activity
    • has_input UniProtKB:P29350
  • MF: GO:0097677 STAT family protein binding
    • has_input UniProtKB:P40763

BP terms to describe regulation of pathway and involvement in processes:

  • BP: GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT
  • BP: GO0097028 dendritic cell differentiation