Multi-layered dosage compensation of the avian Z chromosome by increased transcriptional burst frequency and elevated translational rates

Natali Papanicolaou, Antonio Lentini, Sebastian Wettersten, Michael Hagemann-Jensen, Annika Krüger, Jilin Zhang, Christos Coucoravas, Ioannis Petrosian, Xian Xin, Ilhan Ceyhan, Joanna Rorbach, Dominic Wright and Björn Reinius ()
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Natali Papanicolaou: Karolinska Institutet
Antonio Lentini: Karolinska Institutet
Sebastian Wettersten: Karolinska Institutet
Michael Hagemann-Jensen: Karolinska Institutet
Annika Krüger: Karolinska Institutet
Jilin Zhang: Karolinska Institutet
Christos Coucoravas: Karolinska Institutet
Ioannis Petrosian: Karolinska Institutet
Xian Xin: Karolinska Institutet
Ilhan Ceyhan: Karolinska Institutet
Joanna Rorbach: Karolinska Institutet
Dominic Wright: Linköping University
Björn Reinius: Karolinska Institutet

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Sex-chromosome dosage poses a challenge for heterogametic species in maintaining the proper balance 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 asymmetries in avian cells. Through comprehensive allele-resolved multiome analyses, we examine dosage compensation in female (ZW), male (ZZ), and rare intersex (ZZW) chicken. Our data reveal that females upregulate their single Z chromosome through increased transcriptional burst frequency, mirroring mammalian X upregulation. Z-protein levels are further balanced in females through enhanced translation efficiency. Additionally, we present a global analysis of promoter elements regulating transcriptional burst kinetics in birds, revealing evolutionary conservation of the genomic encoding of burst kinetics between birds and mammals. Our study provides insights into the regulation of avian dosage compensation, and when considering all regulatory layers collectively, an unexpected similarity between avian and mammalian dosage compensation becomes apparent.

Date: 2025
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DOI: 10.1038/s41467-025-64817-w

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