Age-dependent expression pattern in the mammalian brain of a novel, small peptide encoded in the 22q11.2 deletion syndrome region

Kragness, Sabrina; Harrison, Mark A.; Westmoreland, Joby J.; Burstain, Adam; Earls, Laurie R.

doi:10.1016/j.gep.2018.03.004

Cited by 5 publications

(7 citation statements)

References 52 publications

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“…nORFs can encode functional protein-like structures that may play a role in disease [ 20 ]. For example, a novel transcript was found to be expressed in a 22q11 deletion syndrome brain [ 50 ].…”

Section: Introductionmentioning

confidence: 99%

Novel open reading frames in human accelerated regions and transposable elements reveal new leads to understand schizophrenia and bipolar disorder

et al. 2021

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Schizophrenia (SCZ) and bipolar disorder are debilitating neuropsychiatric disorders arising from a combination of environmental and genetic factors. Novel open reading frames (nORFs) are genomic loci that give rise to previously uncharacterized transcripts and protein products. In our previous work, we have shown that nORFs can be biologically regulated and that they may play a role in cancer and rare diseases. More importantly, we have shown that nORFs may emerge in accelerated regions of the genome giving rise to species-specific functions. We hypothesize that nORFs represent a potentially important group of biological factors that may contribute to SCZ and bipolar disorder pathophysiology. Human accelerated regions (HARs) are genomic features showing human-lineage-specific rapid evolution that may be involved in biological regulation and have additionally been found to associate with SCZ genes. Transposable elements (TEs) are another set of genomic features that have been shown to regulate gene expression. As with HARs, their relevance to SCZ has also been suggested. Here, nORFs are investigated in the context of HARs and TEs. This work shows that nORFs whose expression is disrupted in SCZ and bipolar disorder are in close proximity to HARs and TEs and that some of them are significantly associated with SCZ and bipolar disorder genomic hotspots. We also show that nORF encoded proteins can form structures and potentially constitute novel drug targets.

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Section: Introductionmentioning

confidence: 99%

Novel open reading frames in human accelerated regions and transposable elements reveal new leads to understand schizophrenia and bipolar disorder

et al. 2021

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“…The Pants SOG-Y transgenic mouse line to study endogenous Pants Previously, we showed in mice that Pants is expressed preferentially in areas CA3 and CA2 of the hippocampus, and that there is an upregulation of Pants peptide in these regions that is most prominent in the stratum lucidum between 8 and 16 weeks of age (19). However, as with other micropeptides studied (20), Pants is expressed at low levels and is poorly immunogenic, so antibody signal is low in most applications.…”

Section: Resultsmentioning

confidence: 99%

An Rtn4/Nogo-A-interacting micropeptide modulates synaptic plasticity with age

Kragness

Clark

Mullin

et al. 2022

Preprint

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100-250 amino acid 'micropeptides' are hidden throughout mammalian genomes, though few functional studies of micropeptides are published. Here, we describe a micropeptide known as the Plasticity Associated Neural Transcript Short (Pants), located in the 22q11.2 region of the human genome, the microdeletion of which conveys a high risk for schizophrenia. Our data show that Pants is upregulated in early adulthood in the mossy fiber circuit of the hippocampus, where it exerts a powerful negative effect on long-term potentiation (LTP). Pants is secreted from neurons, where it associates with synapses but is rapidly degraded with stimulation. Pants dynamically interacts with Rtn4/Nogo, a well-studied regulator of adult plasticity. This study shows that neural micropeptides can act as architectural modules that increase the diversity of the known proteome.

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“…However, this method proved incorrect since we were calling transcripts which encompassed nORFs while allowing for nORF overlap with the transcript intron, meaning, the nORF sequence would not be processed into the mature transcript. We, therefore, use GffCompare 25,42 , since it identifies nORF-transcript matches based on intron chain overlap and thereby ensures that the nORF exons are encompassed within the identified 13 transcripts. We introduced additional processing steps on the GffCompare result to identify these transcripts as detailed in the next section.…”

Section: The Perils Of Norf Identification Using Transcript Datamentioning

confidence: 99%

“…nORF products regulate plant morphogenesis and were also shown to regulate epidermal differentiation in Drosophila through the modification of a transcription factor called Shavenbaby 11,12 . A mouse nORF called 'Pants', in a region orthologous to the 22q11.2 locus in humans, was identified with potential roles in hippocampal behaviour and a 68-aa protein called 'NoBody' in humans was found to manage the destruction of faulty mRNA in the cell by preventing the formation of P-bodies 9,13 . Importantly, previous study from our lab demonstrated that nORF products from several noncoding regions in mouse neurons are not only translated but can also be biochemically regulated 4,8 .…”

Section: Introductionmentioning

confidence: 99%

Use of short-read RNA-Seq data to identify transcripts that can translate novel ORFs

Erady

Puntambekar

Prabakaran

2020

Preprint

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Identification of as of yet unannotated or undefined novel open reading frames (nORFs) and exploration of their functions in multiple organisms has revealed that vast regions of the genome have remained unexplored or 'hidden'. Present within both protein-coding and noncoding regions, these nORFs signify the presence of a much more diverse proteome than previously expected. Given the need to study nORFs further, proper identification strategies must be in place, especially because they cannot be identified using conventional gene signatures. Although Ribo-Seq and proteogenomics are frequently used to identify and investigate nORFs, in this study, we propose a workflow for identifying nORF containing transcripts using our precompiled database of nORFs with translational evidence, using sample transcript information. Further, we discuss the potential uses of this identification, the caveats involved in such a transcript identification and finally present a few representative results from our analysis of naive mouse B and T cells, human post-mortem brain and cichlid fish transcriptome. Our proposed workflow can identify noncoding transcripts that can potentially translate intronic, intergenic and several other classes of nORFs. One-line summary:A systematic workflow to identify nORF containing transcripts using sample transcript information.

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Age-dependent expression pattern in the mammalian brain of a novel, small peptide encoded in the 22q11.2 deletion syndrome region

Cited by 5 publications

References 52 publications

Novel open reading frames in human accelerated regions and transposable elements reveal new leads to understand schizophrenia and bipolar disorder

Novel open reading frames in human accelerated regions and transposable elements reveal new leads to understand schizophrenia and bipolar disorder

An Rtn4/Nogo-A-interacting micropeptide modulates synaptic plasticity with age

Use of short-read RNA-Seq data to identify transcripts that can translate novel ORFs

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