Analysis of human ES cell differentiation establishes that the dominant isoforms of the lncRNAs RMST and FIRRE are circular

Osagie G. Izuogu, Abd A. Alhasan, Carla Mellough, Joseph Collin, Richard Gallon, Jonathon Hyslop, Francesco K. Mastrorosa, Ingrid Ehrmann, Majlinda Lako, David J. Elliott, Mauro Santibanez-Koref, Michael S. Jackson

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background: Circular RNAs (circRNAs) are predominantly derived from protein coding genes, and some can act as microRNA sponges or transcriptional regulators. Changes in circRNA levels have been identified during human development which may be functionally important, but lineage-specific analyses are currently lacking. To address this, we performed RNAseq analysis of human embryonic stem (ES) cells differentiated for 90 days towards 3D laminated retina.

Results: A transcriptome-wide increase in circRNA expression, size, and exon count was observed, with circRNA levels reaching a plateau by day 45. Parallel statistical analyses, controlling for sample and locus specific effects, identified 239 circRNAs with expression changes distinct from the transcriptome-wide pattern, but these all also increased in abundance over time. Surprisingly, circRNAs derived from long non-coding RNAs (lncRNAs) were found to account for a significantly larger proportion of transcripts from their loci of origin than circRNAs from coding genes. The most abundant, circRMST:E12-E6, showed a > 100X increase during differentiation accompanied by an isoform switch, and accounts for > 99% of RMST transcripts in many adult tissues. The second most abundant, circFIRRE:E10-E5, accounts for > 98% of FIRRE transcripts in differentiating human ES cells, and is one of 39 FIRRE circRNAs, many of which include multiple unannotated exons.

Conclusions: Our results suggest that during human ES cell differentiation, changes in circRNA levels are primarily globally controlled. They also suggest that RMST and FIRRE, genes with established roles in neurogenesis and topological organisation of chromosomal domains respectively, are processed as circular lncRNAs with only minor linear species.

Original languageEnglish
Article number276
Number of pages18
JournalBMC Genomics
Volume19
DOIs
Publication statusPublished - 20 Apr 2018

Cite this

Izuogu, Osagie G. ; Alhasan, Abd A. ; Mellough, Carla ; Collin, Joseph ; Gallon, Richard ; Hyslop, Jonathon ; Mastrorosa, Francesco K. ; Ehrmann, Ingrid ; Lako, Majlinda ; Elliott, David J. ; Santibanez-Koref, Mauro ; Jackson, Michael S. / Analysis of human ES cell differentiation establishes that the dominant isoforms of the lncRNAs RMST and FIRRE are circular. In: BMC Genomics. 2018 ; Vol. 19.
@article{4df07d75ab7943559e80e146dff17219,
title = "Analysis of human ES cell differentiation establishes that the dominant isoforms of the lncRNAs RMST and FIRRE are circular",
abstract = "Background: Circular RNAs (circRNAs) are predominantly derived from protein coding genes, and some can act as microRNA sponges or transcriptional regulators. Changes in circRNA levels have been identified during human development which may be functionally important, but lineage-specific analyses are currently lacking. To address this, we performed RNAseq analysis of human embryonic stem (ES) cells differentiated for 90 days towards 3D laminated retina.Results: A transcriptome-wide increase in circRNA expression, size, and exon count was observed, with circRNA levels reaching a plateau by day 45. Parallel statistical analyses, controlling for sample and locus specific effects, identified 239 circRNAs with expression changes distinct from the transcriptome-wide pattern, but these all also increased in abundance over time. Surprisingly, circRNAs derived from long non-coding RNAs (lncRNAs) were found to account for a significantly larger proportion of transcripts from their loci of origin than circRNAs from coding genes. The most abundant, circRMST:E12-E6, showed a > 100X increase during differentiation accompanied by an isoform switch, and accounts for > 99{\%} of RMST transcripts in many adult tissues. The second most abundant, circFIRRE:E10-E5, accounts for > 98{\%} of FIRRE transcripts in differentiating human ES cells, and is one of 39 FIRRE circRNAs, many of which include multiple unannotated exons.Conclusions: Our results suggest that during human ES cell differentiation, changes in circRNA levels are primarily globally controlled. They also suggest that RMST and FIRRE, genes with established roles in neurogenesis and topological organisation of chromosomal domains respectively, are processed as circular lncRNAs with only minor linear species.",
keywords = "EXON CIRCULARIZATION, NONCODING RNAS, MESSENGER-RNAS, HUMAN GENOME, STEM-CELLS, REVEALS, GENE, EXPRESSION, IDENTIFICATION, ABUNDANT",
author = "Izuogu, {Osagie G.} and Alhasan, {Abd A.} and Carla Mellough and Joseph Collin and Richard Gallon and Jonathon Hyslop and Mastrorosa, {Francesco K.} and Ingrid Ehrmann and Majlinda Lako and Elliott, {David J.} and Mauro Santibanez-Koref and Jackson, {Michael S.}",
year = "2018",
month = "4",
day = "20",
doi = "10.1186/s12864-018-4660-7",
language = "English",
volume = "19",
journal = "BMC Genomics",
issn = "1471-2164",
publisher = "BioMed Central",

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Izuogu, OG, Alhasan, AA, Mellough, C, Collin, J, Gallon, R, Hyslop, J, Mastrorosa, FK, Ehrmann, I, Lako, M, Elliott, DJ, Santibanez-Koref, M & Jackson, MS 2018, 'Analysis of human ES cell differentiation establishes that the dominant isoforms of the lncRNAs RMST and FIRRE are circular' BMC Genomics, vol. 19, 276. https://doi.org/10.1186/s12864-018-4660-7

Analysis of human ES cell differentiation establishes that the dominant isoforms of the lncRNAs RMST and FIRRE are circular. / Izuogu, Osagie G.; Alhasan, Abd A.; Mellough, Carla; Collin, Joseph; Gallon, Richard; Hyslop, Jonathon; Mastrorosa, Francesco K.; Ehrmann, Ingrid; Lako, Majlinda; Elliott, David J.; Santibanez-Koref, Mauro; Jackson, Michael S.

In: BMC Genomics, Vol. 19, 276, 20.04.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Analysis of human ES cell differentiation establishes that the dominant isoforms of the lncRNAs RMST and FIRRE are circular

AU - Izuogu, Osagie G.

AU - Alhasan, Abd A.

AU - Mellough, Carla

AU - Collin, Joseph

AU - Gallon, Richard

AU - Hyslop, Jonathon

AU - Mastrorosa, Francesco K.

AU - Ehrmann, Ingrid

AU - Lako, Majlinda

AU - Elliott, David J.

AU - Santibanez-Koref, Mauro

AU - Jackson, Michael S.

PY - 2018/4/20

Y1 - 2018/4/20

N2 - Background: Circular RNAs (circRNAs) are predominantly derived from protein coding genes, and some can act as microRNA sponges or transcriptional regulators. Changes in circRNA levels have been identified during human development which may be functionally important, but lineage-specific analyses are currently lacking. To address this, we performed RNAseq analysis of human embryonic stem (ES) cells differentiated for 90 days towards 3D laminated retina.Results: A transcriptome-wide increase in circRNA expression, size, and exon count was observed, with circRNA levels reaching a plateau by day 45. Parallel statistical analyses, controlling for sample and locus specific effects, identified 239 circRNAs with expression changes distinct from the transcriptome-wide pattern, but these all also increased in abundance over time. Surprisingly, circRNAs derived from long non-coding RNAs (lncRNAs) were found to account for a significantly larger proportion of transcripts from their loci of origin than circRNAs from coding genes. The most abundant, circRMST:E12-E6, showed a > 100X increase during differentiation accompanied by an isoform switch, and accounts for > 99% of RMST transcripts in many adult tissues. The second most abundant, circFIRRE:E10-E5, accounts for > 98% of FIRRE transcripts in differentiating human ES cells, and is one of 39 FIRRE circRNAs, many of which include multiple unannotated exons.Conclusions: Our results suggest that during human ES cell differentiation, changes in circRNA levels are primarily globally controlled. They also suggest that RMST and FIRRE, genes with established roles in neurogenesis and topological organisation of chromosomal domains respectively, are processed as circular lncRNAs with only minor linear species.

AB - Background: Circular RNAs (circRNAs) are predominantly derived from protein coding genes, and some can act as microRNA sponges or transcriptional regulators. Changes in circRNA levels have been identified during human development which may be functionally important, but lineage-specific analyses are currently lacking. To address this, we performed RNAseq analysis of human embryonic stem (ES) cells differentiated for 90 days towards 3D laminated retina.Results: A transcriptome-wide increase in circRNA expression, size, and exon count was observed, with circRNA levels reaching a plateau by day 45. Parallel statistical analyses, controlling for sample and locus specific effects, identified 239 circRNAs with expression changes distinct from the transcriptome-wide pattern, but these all also increased in abundance over time. Surprisingly, circRNAs derived from long non-coding RNAs (lncRNAs) were found to account for a significantly larger proportion of transcripts from their loci of origin than circRNAs from coding genes. The most abundant, circRMST:E12-E6, showed a > 100X increase during differentiation accompanied by an isoform switch, and accounts for > 99% of RMST transcripts in many adult tissues. The second most abundant, circFIRRE:E10-E5, accounts for > 98% of FIRRE transcripts in differentiating human ES cells, and is one of 39 FIRRE circRNAs, many of which include multiple unannotated exons.Conclusions: Our results suggest that during human ES cell differentiation, changes in circRNA levels are primarily globally controlled. They also suggest that RMST and FIRRE, genes with established roles in neurogenesis and topological organisation of chromosomal domains respectively, are processed as circular lncRNAs with only minor linear species.

KW - EXON CIRCULARIZATION

KW - NONCODING RNAS

KW - MESSENGER-RNAS

KW - HUMAN GENOME

KW - STEM-CELLS

KW - REVEALS

KW - GENE

KW - EXPRESSION

KW - IDENTIFICATION

KW - ABUNDANT

U2 - 10.1186/s12864-018-4660-7

DO - 10.1186/s12864-018-4660-7

M3 - Article

VL - 19

JO - BMC Genomics

JF - BMC Genomics

SN - 1471-2164

M1 - 276

ER -