TY - JOUR
T1 - Reduced LHFPL3-AS2 lncRNA expression is linked to altered epithelial polarity and proliferation, and to ileal ulceration in Crohn disease
AU - Sosnovski, Katya E.
AU - Braun, Tzipi
AU - Amir, Amnon
AU - BenShoshan, Marina
AU - Abbas-Egbariya, Haya
AU - Ben-Yishay, Rakefet
AU - Anafi, Liat
AU - Avivi, Camilla
AU - Barshack, Iris
AU - Denson, Lee A.
AU - Haberman, Yael
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Disruption of intestinal epithelial functions is linked to Crohn disease (CD) pathogenesis. We identified a widespread reduction in the expression of long non-coding RNAs (lncRNAs) including LHFPL3-AS2 in the treatment-naïve CD ileum of the RISK pediatric cohort. We validated the reduction of LHFPL3-AS2 in adult CD and noted a further reduction in patients with more severe CD from the RISK cohort. LHFPL3-AS2 knockdown in Caco-2 cells robustly affected epithelial monolayer morphogenesis with markedly reduced confluency and spreading, showing atypical rounding, and clumping. mRNA-seq analysis of LHFPL3-AS2 knockdown cells highlighted the reduction of genes and pathways linked with apical polarity, actin bundles, morphogenesis, and the b-catenin-TCF4 complex. LHFPL3-AS2 knockdown significantly reduced the ability of cells to form an internal lumen within the 3-dimensional (3D) cyst model, with mislocalization of actin and adherent and tight junction proteins, affecting epithelial polarity. LHFPL3-AS2 knockdown also resulted in defective mitotic spindle formation and consequent reduction in epithelial proliferation. Altogether, we show that LHFPL3-AS2 reduction affects epithelial morphogenesis, polarity, mitotic spindle formation, and proliferation, which are key processes in maintaining epithelial homeostasis in CD. Reduced expression of LHFPL3-AS2 in CD patients and its further reduction with ileal ulceration outcome, emphasizes its significance in this context.
AB - Disruption of intestinal epithelial functions is linked to Crohn disease (CD) pathogenesis. We identified a widespread reduction in the expression of long non-coding RNAs (lncRNAs) including LHFPL3-AS2 in the treatment-naïve CD ileum of the RISK pediatric cohort. We validated the reduction of LHFPL3-AS2 in adult CD and noted a further reduction in patients with more severe CD from the RISK cohort. LHFPL3-AS2 knockdown in Caco-2 cells robustly affected epithelial monolayer morphogenesis with markedly reduced confluency and spreading, showing atypical rounding, and clumping. mRNA-seq analysis of LHFPL3-AS2 knockdown cells highlighted the reduction of genes and pathways linked with apical polarity, actin bundles, morphogenesis, and the b-catenin-TCF4 complex. LHFPL3-AS2 knockdown significantly reduced the ability of cells to form an internal lumen within the 3-dimensional (3D) cyst model, with mislocalization of actin and adherent and tight junction proteins, affecting epithelial polarity. LHFPL3-AS2 knockdown also resulted in defective mitotic spindle formation and consequent reduction in epithelial proliferation. Altogether, we show that LHFPL3-AS2 reduction affects epithelial morphogenesis, polarity, mitotic spindle formation, and proliferation, which are key processes in maintaining epithelial homeostasis in CD. Reduced expression of LHFPL3-AS2 in CD patients and its further reduction with ileal ulceration outcome, emphasizes its significance in this context.
UR - http://www.scopus.com/inward/record.url?scp=85177671661&partnerID=8YFLogxK
U2 - 10.1038/s41598-023-47997-7
DO - 10.1038/s41598-023-47997-7
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C2 - 37993670
AN - SCOPUS:85177671661
SN - 2045-2322
VL - 13
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 20513
ER -