Biology subjects

Woo, Q. Y.

Publications and source records attributed to Woo, Q. Y..

3 recordsLinked to original sources

bioRxiv2025

Methylation mimic mutations of progesterone receptor AF1 impair gene-specific regulation through stabilized chromatin interactions

Progesterone receptor (PR) is a nuclear receptor that regulates gene transcription through recruiting coregulators and general transcription factors by activation functions AF1 and AF2. AF1 localizes to the non-conserved and disordered N terminal domain and is believed to facilitate tissue- and gene-specific activity. Our previous proteomic analysis identified three key functional residues (K464, K481 and R492) of AF1 that are monomethylated. Mutations of KKR to phenylalanine (FFF) that mimic methylation created hypoactive PR, whereas KKR/QQQ mutations generated hyperactive PR in gene reporter assays. The current study investigated specific involvement of AF1 in PR regulation of gene expression in breast cancer cells. AF1-FFF mutations attenuated progestin induced growth regulation, cell adhesion and apoptosis and AF1-QQQ mutation enhanced these effects. Genome-wide expression analysis showed attenuated gene regulation by AF1-FFF of two thirds of PR target genes including genes involved in hypoxia and TNF signalling via NFKB. Unexpectedly, AF1-FFF mutations had little effect on ligand-independent gene regulation, suggesting distinct mechanisms of gene regulation by liganded and unliganded PR. Intriguingly, impaired activity of methylation mimic mutant PR-FFF is associated with higher enhancer binding peaks in ChIP-Seq analysis. This corresponds to a stronger association of AF1-FFF with SRC-1 and AF2 as we previously reported. We propose that methylation mimic AF1 mutant impairs regulation of a subset of genes through tighter coregulator binding which restricts the dynamics of the disassembly of transcription complex.

molecular biology↗

bioRxiv2025

Impact of Choline intake during pregnancy on maternal cognition and hippocampal gene signature in old age

Women are twice as likely to have Alzheimers disease (AD) than men and multiparity has been suggested to be a risk factor for dementia. The present study evaluated whether the lack of certain nutrients during pregnancy influences cognition while pregnant and in old age in mouse model. Non-targeted NMR analysis revealed significantly lower levels of numerous plasma nutrients and metabolites including choline and its derivatives on gestation day 7 compared to day 1. Novel object recognition and Morris Water Maze tests revealed impaired cognition in pregnant mice compared to nonpregnant controls. Choline deprivation worsened the cognitive impairment during pregnancy and choline supplementation alleviated it. Furthermore, choline availability during pregnancy affected cognition and general health in old age, with mice given a choline-deficient diet during pregnancy performed more poorly. RNA-Seq analysis indicates lasting effect of choline intake during pregnancy on hippocampal gene signatures in old age. Choline deprivation was associated with more upregulation of proinflammatory genes, whereas choline supplementation showed upregulation of neuroprotective genes such as Prl, Gh, and hemoglobin (Hba and Hbb subunits). Together, the study shows that choline supplementation benefits cognitive health in women during pregnancy and in old age.

animal behavior and cognition↗

bioRxiv2025

Omics analysis reveals striking effects of progesterone receptor on mitochondria and mitochondria-mediated apoptosis independent of caspases in Breast Cancer cells

The role of progesterone receptor (PR) in breast cancer remains controversial with conflicting reports from clinical and laboratory studies. To address these discrepancies, we conducted an integrated omics analysis of effects of agonist-activated PR in MCF-7 cells with elevated PR expression. PR agonist R5020 exerted strong antiproliferative and proapoptotic effects in these cells. Quantitative proteomics identified 4,915 PR-regulated proteins and 678 phosphorylated peptides, with nearly 100% verifiable rate by Western blotting analysis. The proteomics data was closely correlated with transcriptomic data. Key pathways upregulated included hypoxia, p53 signalling, TNFA signalling via NFKB, epithelial-mesenchymal transition, and KRAS signalling, while E2F targets, G2/M checkpoint, and mitotic spindle assembly were downregulated. R5020 broadly suppressed cell cycle regulators, including CDKs, cyclins, DNA replication proteins, and all components of the Ndc80 complex and chromosomal passenger complexes. Concurrently, it elicited significant changes in 200 mitochondrial proteins, upregulating many proapoptotic factors (e.g., BNIP3, NIX, AIF/AIFM1, AIFM2, ENDOG, HtrA2/Omi, Smac/DIABLO) and downregulating anti-apoptotic proteins (BCL-2, BCL-XL). This culminated in mitochondria-mediated apoptosis independent of effector caspases. The omics analysis also detected previously reported upregulation of pro-growth proteins such as EGFR, IRS2, and CCND1, but the upregulation was functionally futile and inhibitory phosphorylation of IRS2 at S306 increased 4-fold. In conclusion, this omics study achieved to date the most comprehensive and holistic understanding of PR-regulated proteins and molecular networks that are strongly anti-proliferative and proapoptotic with significant involvement of mitochondria. These findings suggest that pure PR agonists warrant evaluation as first-line endocrine therapy for breast cancer with high PR expression.

cancer biology↗