Non-Canonical and Sexually Dimorphic X Dosage Compensation States in the Mouse and Human Germline

Dev Cell. 2017 Feb 6;40(3):289-301.e3. doi: 10.1016/j.devcel.2016.12.023. Epub 2017 Jan 26.

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.

Keywords: X inactivation; X upregulation; dosage compensation; genome-wide reprogramming; germline development; sex chromosomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cellular Reprogramming / genetics
  • Chromosomes, Human, X / genetics*
  • Databases, Genetic
  • Dosage Compensation, Genetic*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Germ Cells / cytology
  • Germ Cells / metabolism*
  • Gonads / cytology
  • Gonads / metabolism
  • Humans
  • Male
  • Mice
  • Models, Genetic
  • Sequence Analysis, RNA
  • Sex Characteristics*
  • Up-Regulation / genetics
  • X Chromosome / genetics*