BCAS2 promotes primitive hematopoiesis by sequestering β-catenin within the nucleus
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ABSTRACT:
PROVIDER: PRJNA1262902 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33570992_1.fastq.gz | Fastqsanger.gz | |||
| SRR33570992_2.fastq.gz | Fastqsanger.gz | |||
| SRR33570993_1.fastq.gz | Fastqsanger.gz | |||
| SRR33570993_2.fastq.gz | Fastqsanger.gz |
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Project description:Breast carcinoma amplified sequence 2 (BCAS2), a core component of the hPrP19 complex, plays crucial roles in various physiological and pathological processes. However, whether BCAS2 has functions other than being a key RNA-splicing regulator within the nucleus remains unknown. Here, we show that BCAS2 is essential for primitive hematopoiesis in zebrafish and mouse embryos. The activation of Wnt/β-catenin signal, which is required for hematopoietic progenitor differentiation, is significantly decreased upon depletion of bcas2 in zebrafish embryos and mouse embryonic fibroblasts (MEFs). Interestingly, BCAS2 deficiency has no obvious impact on the splicing efficiency of β-catenin pre-mRNA, while significantly attenuating β-catenin nuclear accumulation. Moreover, we find that BCAS2 directly binds to β-catenin via its coiled-coil domains, thereby sequestering β-catenin within the nucleus. Thus, our results uncover a previously unknown function of BCAS2 in promoting Wnt signaling by enhancing β-catenin nuclear retention during primitive hematopoiesis.
2025-06-05 | GSE297155 | GEO
Project description:The splicing factor Bcas2 is involved in several biological processes including tumorigenesis, gametogenesis, and hematopoiesis. The alternative splicing events and downstream genes regulated by Bcas2 have not yet been investigated at the transcriptome level in zebrafish. In this study, we conducted RNA-sequencing analysis on the WT and bcas2 knockout zebrafish embryos (3 dpf) to identify the global differentially expressed genes (DEGs) and differential splicing events (DSEs). 868 DEGs (293 up and 575 down) were identified and genes related to spliceosome, mRNA splicing, and mRNA processing were significantly upregulated, suggesting a negative feedback of the splicing pathway. Besides, 664 DSEs related to 593 genes were identified and sequence signature analysis of these DSEs revealed that the alternatively spliced exons affected by bcas2 knockout have relatively shorter length, longer upstream and downstream introns, and weaker 5’ or 3’ splicing sites, when compared with the control exons. Furthermore, we demonstrated that the exon 5 of ikzf1 gene, a transcription factor related to lymphocyte differentiation, was preferably skipped in the bcas2 knockout embryos, resulting in the deletion of 11 aa between the two conserved zinc finger domains of Ikzf1. Accordingly, several downstream genes, such as rasgrp2 and rgs2, were significantly downregulated and the lymphocyte generation was impaired in the bcas2 knockout embryos. Taken together, our work depicts the global changes of gene expression and alternative splicing caused by bcas2 knockout in zebrafish embryos and reveals an important role of Bcas2-regulated alternative splicing of ikzf1 in lymphoid hematopoiesis.
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Project description:Previously, we have confirmed the tumor suppressive role of Estrogen Related Receptor β (ERRβ) in breast cancer by modulation of ER transcriptional activities on Breast Cancer Amplified Sequence 2 (BCAS2) and Follistatin(FST).In the mentioned study, we proved downregulation of Cyclin D1 by BCAS2.In the previous report, we have also proved downregulation of FST by BCAS2 through inhibition of β-catenin/TCF-4 complex recruitment on FST promoter. Interestingly, Cyclin D1 induction by FST has been also reported by a different group.Recently, Cyclin D1 expression has been found to be associated with DICER1 induction. Hence it may be speculated, that a part of miRNA population, which involves Dicer for processing, is regulated by BCAS2. And it is also possible, that FST may oppose the effect of BCAS2 on those Dicer-processed miRNAs.This Dicer-regulation by Cyclin D1was reported in Luminal A type of breast cancer. Hence, we chose MCF-7 breast cancer cells for miRNA profiling post knocking down BCAS2 and FST.
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Project description:Canonical Wnt and Nodal signaling are both required for induction of the primitive streak (PS), which guides organization of the early embryo. The Wnt effector β-catenin is thought to function in these early lineage specification decisions via transcriptional activation of Nodal signaling. Here, we demonstrate a broader role for β-catenin in PS formation by analyzing its genome-wide binding in a human embryonic stem cell model of PS induction. β-catenin occupies regulatory regions in numerous PS and neural crest genes, and direct interactions between β-catenin and the Nodal effectors SMAD2/3 are required at these regions for PS gene activation. Furthermore, OCT4 binding in proximity to these sites is likewise required for PS induction, suggesting a collaborative interaction between β-catenin and OCT4. Induction of neural crest genes by β-catenin is repressed by SMAD2/3, ensuring proper lineage specification. This study provides mechanistic insight into how Wnt signaling controls early cell lineage decisions. Examination of β-catenin binding in hESC incubated in media control (RPMI), media containing CHIR or CHIR+SB for 6h and analyzed by ChIP-sequencing
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Project description:Granulosa cell proliferation and differentiation are essential for follicle development. Breast cancer amplified sequence 2 (BCAS2) is necessary for spermatogenesis, oocyte development, and maintaining the genome integrity of early embryos in mice. However, the function of BCAS2 in granulosa cells is still unknown. We show that conditional disruption of BCAS2 causes follicles development failure; cell proliferation markers PCNA and Ki67 positive cell ratio are unchanged in granulosa cells. However, specific deletion of BCAS2 causes BrdU positive cell ratio to decrease, cell cycle arrest appearance, DNA damage, and cell apoptosis increase in granulosa cells, RPA1 was abnormally stained in granulosa cells. Furthermore, RNA-Seq results reveal that knockout of BCAS2 results in cellular senescence gene unusual expression. BCAS2 participates in the PRP19 complex to mediate alternative splicing (AS) of E2f3 and Flt3l mRNA to inhibit the cell cycle. Knock down of BCAS2 results in a significantly decrease of BrdU positive cell ratio in Human granulosa-like tumor(KGN) cell line. Thus, BCAS2 regulates granulosa cell proliferation, DNA damage repair, and cell apoptosis. BCAS2 is vital for female fertility.
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