Expression in Aneuploid Drosophila S2 Cells

• Published in: PLoS biology Vol. 8; no. 2; p. e1000320
• Main Authors: Zhang, Yu, Malone, John H., Powell, Sara K., Periwal, Vipul, Spana, Eric, MacAlpine, David M., Oliver, Brian
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.02.2010; Public Library of Science (PLoS)
• Subjects: Aneuploidy; Animals; Blotting, Western; Cell culture; Cell Line; Chromatin Immunoprecipitation; Chromosomes; Comparative Genomic Hybridization; Compensation; Dosage Compensation, Genetic - genetics; Drosophila; Drosophila - genetics; Drosophila - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Dynamic programming; Experiments; Gene expression; Gene Expression Regulation; Genetic aspects; Genetics; Genetics and Genomics/Cancer Genetics; Genetics and Genomics/Chromosome Biology; Genetics and Genomics/Epigenetics; Genetics and Genomics/Functional Genomics; Genomes; Hypotheses; Insects; Male; Mutation; Oligonucleotide Array Sequence Analysis; Organisms; Risk factors; RNA Interference; Sequence Analysis, DNA; Tumors; X Chromosome - genetics; United States; Cell Line; Drosophila Proteins; Oligonucleotide Array Sequence Analysis; Drosophila; Gene Expression Regulation; Aneuploidy; Male; Sequence Analysis, DNA; Blotting, Western; Dosage Compensation, Genetic; Animals; Chromatin Immunoprecipitation; Comparative Genomic Hybridization; RNA Interference; X Chromosome
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.1000320

Extensive departures from balanced gene dose in aneuploids are highly deleterious. However, we know very little about the relationship between gene copy number and expression in aneuploid cells. We determined copy number and transcript abundance (expression) genome-wide in Drosophila S2 cells by DNA-Seq and RNA-Seq. We found that S2 cells are aneuploid for >43 Mb of the genome, primarily in the range of one to five copies, and show a male genotype ( approximately two X chromosomes and four sets of autosomes, or 2X;4A). Both X chromosomes and autosomes showed expression dosage compensation. X chromosome expression was elevated in a fixed-fold manner regardless of actual gene dose. In engineering terms, the system "anticipates" the perturbation caused by X dose, rather than responding to an error caused by the perturbation. This feed-forward regulation resulted in precise dosage compensation only when X dose was half of the autosome dose. Insufficient compensation occurred at lower X chromosome dose and excessive expression occurred at higher doses. RNAi knockdown of the Male Specific Lethal complex abolished feed-forward regulation. Both autosome and X chromosome genes show Male Specific Lethal-independent compensation that fits a first order dose-response curve. Our data indicate that expression dosage compensation dampens the effect of altered DNA copy number genome-wide. For the X chromosome, compensation includes fixed and dose-dependent components.