Genes

Our review develops a mechanistic hypothesis and does not describe an established pathway. The empirical premise on which it rests, that HPV E6 is expressed in endometrial tissue and degrades p53 at that site, has not been demonstrated in humans. Endometrial expression of leukaemia inhibitory factor (LIF) is required for blastocyst implantation, and in the mouse it is transcribed under the control of p53 acting at a response element in intron 1 that is conserved in the human gene. Human support for the same relationship is genetic rather than biochemical. The TP53 codon 72 polymorphism rs1042522 alters LIF transactivation and has been associated with implantation failure in several cohorts while showing no effect in the largest. Variation in LIF itself at rs929271, and in MDM2, MDM4 and USP7, has been associated with implantation and with later pregnancy maintenance. High-risk human papillomavirus brings a second genome into the same regulatory problem. The E6 oncoprotein recruits the E6-associated protein ubiquitin ligase and directs p53 to proteasomal degradation, and the efficiency of that reaction varies by more than two orders of magnitude across high-risk genotypes and again between natural sequence variants of HPV16 E6. Loss of p53 also raises DNMT1 and removes p53-dependent microRNAs, which places the axis inside the epigenetic programme of the cycling endometrium.

Background/objectives: TEX11 variants are an established cause of male infertility, particularly non-obstructive azoospermia (NOA) with meiotic arrest. However, the pathogenicity of many reported variants and their implications for sperm retrieval remain uncertain. We aimed to reassess TEX11 variant pathogenicity and evaluate evidence relevant to testicular sperm extraction (TESE). Methods: We systematically reassessed reported TEX11 variants by integrating clinical phenotype, testicular histology, computational predictions, functional evidence, and structural modelling of TEX11 interactions with its meiotic partners. Available sperm-retrieval data were also reviewed to assess their relevance for testicular sperm extraction (TESE). Results: Sixty-one unique variants were identified. After reassessment, 22 (36.1%) were classified as pathogenic or likely pathogenic, 27 (44.3%) as benign or likely benign, and 12 (19.7%) as variants of uncertain significance. Truncating variants accounted for most pathogenic variants and were predominantly associated with NOA and meiotic arrest. Among carriers with available histological data, meiotic arrest was the predominant finding (36/45, 80.0%), whereas individually documented sperm retrieval outcomes were limited, precluding reliable variant-specific predictions of TESE success or failure. Conclusions: These findings emphasize the distinction between molecular pathogenicity, histological impairment, and sperm retrieval prognosis. Current evidence does not support using TEX11 genotype alone to contraindicate TESE.

Background/Objectives: Chromatin organization reflects the coordinated activities of histone modifications and chromatin-associated proteins. Inspired by single-cell genomics, we investigated whether genomic bins could be treated as multidimensional observations to identify biologically interpretable chromatin-associated signatures and characterize their genomic patterns across cell types. Methods: We integrated genome-wide profiles of CTCF occupancy and four histone modifications (H3K27ac, H3K9ac, H3K27me3, and H3K9me3) at 1 kb resolution in HCT116 and K562 cells. Unsupervised dimensionality reduction and clustering were used to characterize chromatin-associated signatures. Principal component analysis (PCA) and integration with Hi-C data were used to examine differences between cell lines and associations with local genome architecture. Results: Five clusters of genomic bins were identified, characterized by H3K9me3-enriched, CTCF-enriched, acetylation-enriched, mixed repressive, and H3K27me3-enriched signatures. Among the selected features, H3K27me3 exhibited the greatest separation between HCT116 and K562 in the first two principal components, followed by CTCF. Integration with Hi-C data showed that CTCF-enriched regions were preferentially associated with previously annotated CTCF–CTCF chromatin loop anchors in both cell lines, consistent with the established architectural role of CTCF. Together, these findings highlight distinct chromatin-associated signatures and their relationships with higher-order genome architecture across the two cancer cell lines. Conclusions: Treating genomic bins as multidimensional observations provides a complementary exploratory approach for characterizing chromatin-associated signatures. Our findings illustrate its potential for comparing chromatin-feature organization between cell types and examining relationships with established features of three-dimensional (3D) genome architecture.