Shyamal, S. | bioRxiv Science

bioRxiv2025

HOXA10 is a Temporal Switch in Controlling Decidual Inflammation and Its Dysregulation is Associated with Early Pregnancy Loss

Successful implantation requires precisely timed endometrial inflammation. Although an initial inflammatory burst is essential for implantation, this response must be rapidly resolved for placentation and pregnancy to progress. The mechanisms that coordinate this temporal switch remain poorly understood. Here, we identify the transcription factor HOXA10 as a key regulator of inflammatory transitions in decidual stromal cells and examine how its dysregulation contributes to implantation failure and early pregnancy loss. In mice, HOXA10 expression decreases transiently at implantation and rises again post-implantation. Silencing HOXA10 in human decidualized stromal cells induced a robust pro-inflammatory state, altered integrin and cytoskeletal gene expression, and impaired stromal substrate adhesion. In non-pregnant Hoxa10 hypomorphs, stromal cells exhibited elevated IL1β and TXNIP, activation of the NLRP3/ASC inflammasome, and dysregulation of receptivity markers. During pregnancy, persistent HOXA10 deficiency prevented the resolution of inflammation, resulting in disorganized decidua, defective placentation, infertility, or progressive reproductive decline. To assess translational relevance, we analyzed publicly available bulk and single-cell RNA-seq datasets from first-trimester human decidua and from women with recurrent pregnancy loss (RPL). Single-cell analysis revealed that HOXA10 is selectively low in inflammatory decidual stromal cell clusters, which display concordant upregulation of IL1B, PYCARD, TXNIP, and inflammasome components. Consistently, both bulk and single-cell datasets from women with RPL showed reduced HOXA10 accompanied by increased inflammatory gene expression. Overall, HOXA10 functions as a temporal switch that enables the initial inflammatory activation required for implantation and subsequently suppresses inflammation to support decidual organization, adhesion, and placentation. Loss of this switch leads to persistent decidual inflammation and is associated with pregnancy loss in both mouse models and humans. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/691844v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@ee81b6org.highwire.dtl.DTLVardef@85d84eorg.highwire.dtl.DTLVardef@13c1b6aorg.highwire.dtl.DTLVardef@12bed9b_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2024

Glucose-regulated circular RNA Rabep1 regulates pancreatic beta-cell growth by modulating miR-335-3p/PTEN axis

HighlightsO_LIIdentified circRNAs expressed in {beta}TC6 cell line C_LIO_LIFirst report identifying glucose-regulated circRNAs in pancreatic {beta}-cell C_LIO_LICircRabep1 regulates {beta}-cell growth by binding to miR-335-3p C_LI Circular RNAs (circRNAs) are a large family of closed-loop RNA molecules emerging as novel regulators of gene expression. Although several circRNAs are known to regulate various biological processes, the functions of most circRNAs expressed in pancreatic {beta}-cells remain to be discovered. Since short-term glucose treatment induces pancreatic {beta}-cell growth and promotes insulin production, we wanted to explore the role of glucose-regulated circRNAs in pancreatic {beta}-cell physiology. Our RNA-seq analysis identified more than 300 differentially expressed circRNAs in high-glucose compared to low-glucose treated {beta}TC6 cells. A subset of differentially expressed and abundant circRNAs was validated by various biochemical methods, including circular RNA Rabep1 (circRabep1). Moreover, the downregulation of circRabep1 in high glucose-treated {beta}TC6 cells suggested a possible function in {beta}-cell physiology. Furthermore, analysis of the circRabep1-miRNA-mRNA regulatory network discovered the association of circRabep1 with miR-335-3p, a suppressor of Pten expression. Importantly, inhibition of miRNA function by miR-335-3p inhibitor results in upregulation of PTEN levels, suppressing {beta}-cell growth and proliferation. Furthermore, silencing circRabep1 decreased PTEN expression by sponging miR-335-3p, promoting cell proliferation. We propose that the downregulation of circRabep1 in high-glucose treated {beta}-cell leads to an increase in {beta}-cell proliferation by suppressing PTEN expression through derepression of miR-335-3p. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=62 SRC="FIGDIR/small/600308v1_ufig1.gif" ALT="Figure 1"> View larger version (10K): org.highwire.dtl.DTLVardef@542b03org.highwire.dtl.DTLVardef@1d3f3faorg.highwire.dtl.DTLVardef@36b476org.highwire.dtl.DTLVardef@181c7b4_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO Schematic showing the molecular function of glucose-regulated circRabep1 in pancreatic -cell growth by binding to miR-335-3p. C_FIG

molecular biology↗