Biology subjects

Chakravorty, N.

Publications and source records attributed to Chakravorty, N..

3 recordsLinked to original sources

bioRxiv2025

CircNFATc3 promotes Fetal Hemoglobin induction by regulating let-7b/GATA2 axis

Reactivation of developmentally suppressed fetal hemoglobin (HbF) holds therapeutic promise. However, the post-transcriptional control of regulators that orchestrate {gamma}-globin (HBG1/2) expression is still elusive. This study aims to elucidate the highly understudied role of circular RNA (circRNA), circNFATc3, as post-transcriptional {gamma}-globin regulator. This study evaluates the circNFATc3/let-7b/GATA2 axis and its relationship with HbF induction through computational and experimental molecular and cellular approaches, including gain and loss-of-function studies. These evaluations have revealed that competitive splicing of circNFATc3, at the expense of its linear transcript, sequesters let-7b miRNA, thereby reactivating GATA2-mediated HbF expression. Moreover, transcriptomic profiling of circNFATc3-overexpressed erythroid cells showed that its role is not only restricted to HbF induction but it may play a broader role in erythropoiesis, adding further complexity to the role of this circular transcript. Therefore, our study demonstrates a pivotal role of circNFATc3 as an HbF inducer and places this circRNA as a promising modifier in erythroid transcription programs, opening avenues for novel therapeutic strategies in {beta}-thalassemia.

molecular biology↗

bioRxiv2025

UCA1 lncRNA represses γ-globin expression by sequestering miR-148b, a key post-transcriptional regulator of BCL11A

Fetal hemoglobin (HbF; 2{gamma}2) reactivation is a promising strategy to ameliorate {beta}-hemoglobinopathies. However, limited understanding of {gamma}-globin (HBG1/2) regulation constrains development of therapeutic interventions. BCL11A, a key transcriptional repressor of {gamma}-globin, is central to HbF silencing during adult erythropoiesis. Here, we identify a new post-transcriptional regulatory mechanism involving the lncRNA-UCA1 and miR-148b that modulates BCL11A expression. Using UCA1 knockdown and overexpression strategies, combined with in vivo crosslinking and transcriptomic analyses, we demonstrate that UCA1 functions as a competing endogenous RNA (ceRNA), sequestering miR-148b and thereby attenuating its repressive effect on BCL11A. In the present study, we have elucidated the physiological significance of this interaction in adult erythroid cells, including CD34 HSPCs and HUDEP-2 cells, in which UCA1 depletion led to robust {gamma}-globin induction, a phenotype recapitulated by miR-148b overexpression. These findings uncover a previously unrecognized lncRNA-miRNA-mRNA regulatory axis and highlight the UCA1/miR-148b axis as a potential therapeutic target for HbF reactivation in {beta}-hemoglobinopathies.

genetics↗

bioRxiv2021

Debunking the "junk": Unraveling the role of lncRNA-miRNA-mRNA networks in fetal hemoglobin regulation

Fetal hemoglobin (HbF) induction is considered to be a promising therapeutic strategy to ameliorate the clinical severity of {beta}-hemoglobin disorders, and has gained a significant amount of attention in recent times. Despite the enormous efforts towards the pharmacological intervention of HbF reactivation, progress has been stymied due to limited understanding of {gamma}-globin gene regulation. In this study, we intended to investigate the implications of lncRNA-associated competing endogenous RNA (ceRNA) interactions in HbF regulation. Probe repurposing strategies for extraction of lncRNA signatures and subsequent in silico analysis on publicly available datasets (GSE13284, GSE71935 and GSE7874) enabled us to identify 46 differentially expressed lncRNAs (DElncRNAs). Further, an optimum set of 11 lncRNAs that could distinguish between high HbF and normal conditions were predicted from these DElncRNAs using supervised machine learning and a stepwise selection model. The candidate lncRNAs were then linked with differentially expressed miRNAs and mRNAs to identify lncRNA-miRNA-mRNA ceRNA networks. The network revealed that 2 lncRNAs (UCA1 and ZEB1-AS1) and 4 miRNAs (hsa-miR-19b-3p,hsa-miR-3646,hsa-miR-937 and hsa-miR-548j) sequentially mediate cross-talk among different signaling pathways which provide novel insights into the lncRNA-mediated regulatory mechanisms, and thus lay the foundation of future studies to identify lncRNA-mediated therapeutic targets for HbF reactivation.

bioinformatics↗