title: Non-Canonical and Sexually Dimorphic X Dosage Compensation States in the Mouse and Human Germline.
abstract: Somatic X dosage compensation requires two mechanisms: X inactivation balances X gene output between males (XY) and females (XX), while X upregulation, hypothesized by Ohno and documented in vivo, balances X gene with autosomal gene output. Whether X dosage compensation occurs in germ cells is unclear. We show that mouse and human germ cells exhibit non-canonical X dosage states that differ from the soma and between the sexes. Prior to genome-wide reprogramming, X upregulation is present, consistent with Ohno's hypothesis. Subsequently, however, it is erased. In females, erasure follows loss of X inactivation, causing X dosage excess. Conversely, in males, erasure leads to permanent X dosage decompensation. Sex chromosomally abnormal models exhibit a "sex-reversed" X dosage state: XX males, like XX females, develop X dosage excess, while XO females, like XY males, develop X dosage decompensation. Thus, germline X dosage compensation states are determined by X chromosome number, not phenotypic sex. These unexpected differences in X dosage compensation states between germline and soma offer unique perspectives on sex chromosome infertility.
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, The Ridgeway, Mill Hill, London NW7 1AA, UK; UCL EGA Institute for Women's Health UCL, Medical School Building, 74 Huntley Street, London WC1E 6AU, UK.
authors.forename: Mahesh N
authors.initials: MN
authors.lastname: Sangrithi
authors.affiliation: Friedrich Miescher Institute for Biomedical Research (FMI), 4058 Basel, Switzerland; Swiss Institute of Bioinformatics, 4058 Basel, Switzerland.
authors.forename: Helene
authors.initials: H
authors.lastname: Royo
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Shantha K
authors.initials: SK
authors.lastname: Mahadevaiah
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Obah
authors.initials: O
authors.lastname: Ojarikre
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Leena
authors.initials: L
authors.lastname: Bhaw
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Abdul
authors.initials: A
authors.lastname: Sesay
authors.affiliation: Friedrich Miescher Institute for Biomedical Research (FMI), 4058 Basel, Switzerland.
authors.forename: Antoine H F M
authors.initials: AH
authors.lastname: Peters
authors.affiliation: Friedrich Miescher Institute for Biomedical Research (FMI), 4058 Basel, Switzerland; Swiss Institute of Bioinformatics, 4058 Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Stadler
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, The Ridgeway, Mill Hill, London NW7 1AA, UK. Electronic address: james.turner@crick.ac.uk.
authors.forename: James M A
authors.initials: JM
authors.lastname: Turner
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics*; D030541:Databases, Genetic; D004303:Dosage Compensation, Genetic; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism*; D006066:Gonads / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008957:Models, Genetic; D017423:Sequence Analysis, RNA; D012727:Sex Characteristics; D015854:Up-Regulation / Q000235:genetics; D014960:X Chromosome / Q000235:genetics*
keywords: X inactivation; X upregulation; dosage compensation; genome-wide reprogramming; germline development; sex chromosomes