Biology subjects

Wettersten, S.

Publications and source records attributed to Wettersten, S..

3 recordsLinked to original sources

bioRxiv2025

Dosage responses of aneuploid autosomal chromosomes

Aneuploidy, resulting from segmental or complete chromosomal losses or gains, is generally detrimental to organismal fitness, but is also associated with tumourigenicity. While sex chromosome aneuploidies are well-tolerated due to dedicated allelic dosage compensation mechanisms, the existence of similar regulatory processes for autosomes remains debated. Here, we investigate transcriptional responses to autosomal aneuploidies and find evidence for global dosage compensation across aneuploid chromosomes. Using high-sensitivity, allele-resolved single-cell RNA-seq on monoclonal cell expansions with varying ploidies and degrees of autosomal aneuploidy, we uncover consistent transcriptional compensation upon chromosome losses via increased burst frequency from the remaining allele. This operates in a region-specific manner across both complete and segmental aneuploidies, revealing a previously underappreciated flexibility of dosage response. Complementary proteomics analyses demonstrate additional dosage buffering at the protein level, resulting in near-stoichiometric rebalancing across autosomal aneuploid chromosomes. Analyses of cancer transcriptomes confirms that compensatory mechanisms are active in primary tumours. Our findings reveal extensive dosage compensation as a genome-wide, dynamic, response to gene product imbalance. This mechanism extends beyond sex chromosomes, supports transcriptional homeostasis, and represents a fundamental, evolutionarily conserved mode of transcriptional regulation active across species and in aneuploid cancer cells.

cell biology↗

bioRxiv2024

Z-chromosome dosage compensation and a male-specific lncRNA in octopus

Sex chromosomes typically present as two copies of a large, gene-rich differentiated chromosome in the homogametic sex (e.g. XX in female mammals, ZZ in male birds) but as a single copy in the heterogametic sex, often paired with a sex-specific, degenerated chromosome (XY in male mammals, ZW in female birds). This creates a significant gene product dosage imbalance of the X and Z chromosomes between the sexes as well as between the single sex chromosome and the autosomes in the heterogametic sex, making its resolution essential. Dosage compensation and its molecular mechanisms have primarily been studied in select organisms, such as primates, rodents, birds, fruit flies, and Caenorhabditis elegans, while the extent and mechanisms of dosage compensation remain largely unexplored in the vast majority of animal taxa. Recently, coleoid cephalopods, including octopuses, squids, and cuttlefish, were reported to possess a ZZ/Z0 sex chromosome system1, where males carry two copies of the Z chromosome while females carry only one. However, whether dosage compensation occurs in these species remains unexplored. Here, we show, for the first time, that Z-chromosome dosage compensation is achieved in octopus. Using both original RNA-seq data from O.vulgaris paralarvae as well as publicly available datasets from O.vulgaris and O.sinensis, we report extensive but incomplete dosage compensation of the Z-chromosome in female octopus at the RNA level, similar to Z-chromosome dosage compensation in avian ZW systems. Furthermore, we identify two evolutionarily conserved Z-linked lncRNAs, one featuring strong male-biased expression patterns, that we termed "Zmast" and another with strong female-biased expression patterns that we termed "Zfest". Our results provide the first evidence of sex chromosome dosage compensation in octopus, representing one of the most ancient known animal sex-chromosome systems, and raise the possibility that non-coding RNA may play a role in its regulation, akin that observed in younger animal taxa.

molecular biology↗

bioRxiv2024

Multi-layered dosage compensation of the avian Z chromosome

Sex-chromosome dosage represents a challenge for heterogametic species to maintain correct proportion of gene products across chromosomes in each sex. While therian mammals (XX/XY system) achieve near-perfect balance of X-chromosome mRNAs through X-upregulation and X-inactivation, birds (ZW/ZZ system) have been found to lack efficient compensation at RNA level, challenging the necessity of resolving major gene-dosage discrepancies in avian cells. Through allele-resolved multiome analyses, we comprehensively examined dosage compensation in female (ZW), male (ZZ), and rare intersex (ZZW) chicken. Remarkably, this revealed that females exhibit upregulation of their single Z through increased transcriptional burst frequency similar to mammalian X-upregulation, and that Z-protein levels are further balanced via enhanced translation efficiency in females. Global analyses of transcriptional kinetics elements in birds demonstrate remarkable conservation of the genomic encoding of burst kinetics between mammals and birds. Our study uncovers new mechanisms for achieving sex-chromosome dosage compensation and highlights the importance of gene-dosage balance across diverse species.

molecular biology↗