Biology subjects

Fan, H.-Y.

Publications and source records attributed to Fan, H.-Y..

6 recordsLinked to original sources

bioRxiv2026

DHX36 regulates antral follicle development and ovulation as a non-OSF maternal factor by maintaining oocyte homeostasis and supporting OSF delivery

Healthy ovarian follicle development and ovulation require coordinated communication between oocytes and surrounding somatic cells. Although oocyte-secreted factors (OSFs), such as GDF-9 and BMP-15, are established regulators of this communication, the non-OSF maternal factors that support OSF delivery and signaling during late-stage follicle development remain poorly understood. Here, using an oocyte-specific Dhx36 knockout mouse model, we identify the G-quadruplex (G4) helicase DHX36 as a non-OSF maternal factor required for antral follicle development and hormone-induced ovulation. Dhx36 deficiency caused severe defects in granulosa cell proliferation and cumulus expansion, accompanied by impaired activation of SMAD2/3 and SMAD1/5/8, while ERK1/2 activation remained intact. Although the expression of major OSFs was largely unchanged, Dhx36-deficient oocytes exhibited disrupted microvilli and transzonal projections (TZPs), resulting in defective OSF delivery and impaired oocyte-cumulus communication. Proteomic, lipidomic, and ultrastructural analyses further revealed dysregulated phospholipid metabolism, membrane organization, autophagy, and organelle homeostasis, including abnormal lysosomal, mitochondrial, and endoplasmic reticulum structures. Integrative transcriptomic and proteomic analyses identified concordant downregulation of genes involved in these processes, whose promoters were enriched in potential G4 motifs. Consistently, Dhx36 deficiency was associated with reduced RNA polymerase II activity, while pharmacological G4 stabilization impaired transcription of selected genes. Together, these findings establish DHX36 as a maternal regulator that links oocyte intrinsic homeostasis to intercellular communication, suggesting that DHX36-dependent maintenance of membrane and organelle integrity is essential for OSF delivery, cumulus cell function, antral follicle development, and ovulation.

developmental biology↗

bioRxiv2026

Auranofin potentiates cisplatin response through context-dependent NOTCH-associated signaling states in endometrial cancer

Therapeutic resistance remains a major challenge in advanced and recurrent endometrial cancer (EC). Aberrant NOTCH signaling has been associated with aggressive tumor behavior and therapeutic resistance across multiple malignancies, yet its therapeutic significance in EC remains incompletely defined. We investigated whether auranofin (AuR), a noncanonical modulator of NOTCH signaling through the transcriptional effector RBPJ, alters platinum responsiveness in EC models. Elevated NOTCH3 copy-number was associated with poorer overall survival in the TCGA-UCEC cohort. AuR treatment reduced RBPJ occupancy at canonical NOTCH target loci, including HES1 and HES4, across multiple EC models. Stable NOTCH3 depletion altered AuR responsiveness in a context-dependent manner while significantly enhancing cisplatin (CDDP) sensitivity in AN3CA cells. Pharmacologic AuR treatment similarly potentiated CDDP response in AN3CA cells and AN3CA xenografts, resulting in reduced tumor burden and prolonged endpoint-free survival following combination treatment. In contrast, ARK-1 xenografts demonstrated limited additional benefit from combined AuR plus CDDP therapy despite detectable suppression of RBPJ occupancy. Together, these findings identify context-dependent NOTCH-associated therapeutic vulnerabilities in EC and support further development of biomarker-guided AuR-based platinum-sensitization strategies. Statement of significanceAuranofin suppresses RBPJ-associated transcriptional activity and enhances cisplatin response in biologically distinct subsets of endometrial cancer.

cancer biology↗

bioRxiv2024

N-acetyltransferase 10-mediated mRNA N4-acetylation is Essential for the Translational Regulation During Oocyte Meiotic Maturation in Mice

Mammalian oocyte maturation is driven by the strict translational regulation of maternal mRNAs stored in the cytoplasm. However, the function and mechanism of post-transcriptional chemical modifications, especially the newly identified N4-acetylcytidine (ac4C) modification catalyzed by N-acetyltransferase 10 (NAT10), are unknown. In this study, we developed a low-input ac4C sequencing technology, ac4C LACE-seq, and mapped 8241 ac4C peaks at the whole-transcriptome level using 50 mouse oocytes at the germinal vesicle stage. We profiled the mRNA landscapes of NAT10-interactions and ac4C modifications. The NAT10-interacted and ac4C-modified transcripts are associated with high translation efficiency in oocytes. Oocyte-specific Nat10 knockout wiped out ac4C signals in oocytes and caused severe defects in meiotic maturation and female infertility. ac4C LACE-seq results indicated that Nat10 deletion led to a failure of ac4C deposition on mRNAs encoding key maternal factors, such as MSY2, ZAR1, BTG4, and cyclin B1, which regulate transcriptome stability and maternal-to-zygotic transition. Nat10-deleted oocytes showed decreased mRNA translation efficiency during meiotic maturation, partially due to the direct inhibition of ac4C sites on specific transcripts. In summary, we developed a low-input, high-sensitivity mRNA ac4C profiling approach and highlighted the important physiological function of ac4C in the precise regulation of oocyte meiotic maturation by enhancing translation efficiency.

developmental biology↗

bioRxiv2023

Biallelic Variants in MAD2L1BP (p31comet) Cause Female Infertility Characterized by Oocyte Maturation Arrest

Human oocyte maturation arrest represents one of the severe conditions for female patients with primary infertility. However, the genetic factors underlying this human disease remain largely unknown. The spindle assembly checkpoint (SAC) is an intricate surveillance mechanism that ensures accurate segregation of chromosomes throughout cell cycles. Once the kinetochores of chromosomes are correctly attached to bipolar spindles and the SAC is satisfied, the MAD2L1BP, best known as p31comet, binds MAD2 and recruits the AAA+-ATPase TRIP13 to disassemble the mitotic checkpoint complex (MCC), leading to the cell cycle progression. In this study, by whole-exome sequencing (WES), we identified homozygous and compound heterozygous MAD2L1BP variants in three families with female patients diagnosed with primary infertility owing to oocyte metaphase I (MI) arrest. Functional studies revealed that the protein variants resulting from the C-terminal truncation of MAD2L1BP lost their binding ability to MAD2. cRNA microinjection of full-length or truncated MAD2L1BP uncovered their discordant roles in driving the extrusion of polar body 1 (PB1) in mouse oocytes. Furthermore, the patients oocytes carrying the mutated MAD2L1BP variants resumed polar body extrusion (PBE) when rescued by microinjection of full-length MAD2L1BP cRNAs. Together, our studies identified and characterized novel biallelic variants in MAD2L1BP responsible for human oocyte maturation arrest at MI, and thus prompted new therapeutic avenues for curing female primary infertility.

developmental biology↗

bioRxiv2022

Extensive RNA editing in tomato nuclear genes

MicroTom tomato has a short growth cycle and high transformation efficiency, and is a prospective model plant for studying organ development, metabolism, and plant-microbe interactions. Here, with a newly assembled reference genome for this tomato cultivar and abundant RNA-seq data derived from tissues of different organs/developmental stages/treatments, we constructed multiple gene co-expression networks, which will provide valuable clues for the identification of important genes involved in diverse regulatory pathways during plant growth, e.g., arbuscular mycorrhizal symbiosis and fruit development. Additionally, non-coding RNAs, including miRNAs, lncRNAs and circRNAs were also identified, together with their potential targets. Interacting networks between different types of non-coding RNAs (miRNA-lncRNA), and non-coding RNAs and genes (miRNA-mRNA and lncRNA-mRNA) were constructed as well. Our results and data will provide valuable information for the study of organ differentiation and development of this important fruit. Lastly, we established a database (http://eplant.njau.edu.cn/microTomBase/) with genomic and transcriptomic data, as well as details of gene co-expression and interacting networks on microTom, and this database should be of great value to those who wants to adopt microTom as a model plant for research.

genomics↗

bioRxiv2021

Genome-wide decoupling of H2Aub and H3K27me3 in early mouse development

Polycomb group (PcG) proteins are crucial chromatin regulators during development. H2Aub and H3K27me3 are catalyzed by Polycomb-repressive Complex 1 and 2 (PRC1/2) respectively, and largely overlap in the genome due to mutual recruitment of the two complexes. However, whether PRC1/H2Aub and PRC2/H3K27me3 can function independently remains obscure. Here we uncovered a genome-wide decoupling of H2Aub and H3K27me3 in preimplantation mouse embryos, at both canonical PcG targets and broad distal domains. H2Aub represses future bivalent genes without H3K27me3 but does not contribute to maintenance of H3K27me3-dependent non-canonical imprinting. Our study thus revealed their distinct and independent functions in early mammalian development.

molecular biology↗