Abstract
BackgroundPolycomb-group (PcG) and trithorax-group (trxG) proteins regulate histone methylation to establish repressive and active chromatin configurations at target loci, respectively. These chromatin configurations are passed on from mother to daughter cells, thereby causing heritable changes in gene expression. The activities of PcG and trxG proteins are regulated by a special class of proteins known as Enhancers of trithorax and Polycomb (ETP). The Drosophila gene Additional sex combs (Asx) encodes an ETP protein and mutations in Asx enhance both PcG and trxG mutant phenotypes. The mouse and human genomes each contain three Asx homologues, Asx-like 1, 2, and 3. In order to understand the functions of mammalian Asx-like (Asxl) proteins, we generated an Asxl2 mutant mouse from a gene-trap ES cell line.Methodology/Principal FindingsWe show that the Asxl2 gene trap is expressed at high levels in specific tissues including the heart, the axial skeleton, the neocortex, the retina, spermatogonia and developing oocytes. The gene trap mutation is partially embryonic lethal and approximately half of homozygous animals die before birth. Homozygotes that survive embryogenesis are significantly smaller than controls and have a shortened life span. Asxl2−/− mice display both posterior transformations and anterior transformation in the axial skeleton, suggesting that the loss of Asxl2 disrupts the activities of both PcG and trxG proteins. The PcG-associated histone modification, trimethylation of histone H3 lysine 27, is reduced in Asxl2−/− heart. Necropsy and histological analysis show that mutant mice have enlarged hearts and may have impaired heart function.Conclusions/SignificanceOur results suggest that murine Asxl2 has conserved ETP function and plays dual roles in the promotion of PcG and trxG activity. We have also revealed an unexpected role for Asxl2 in the heart, suggesting that the PcG/trxG system may be involved in the regulation of cardiac function.
Highlights
Polycomb Group (PcG) proteins and their antagonists, trithorax Group proteins, were identified in Drosophila as transcriptional repressors and activators of homeotic genes (Hox genes), respectively [1,2,3]
In the AQ0356 line, the gene trap cassette integrated within the first intron of Asx-like 2 (Asxl2)
Using RT-PCR, we confirmed that transcription of the trapped allele (Asxl22) produces an mRNA in which the first exon of Asxl2 is joined to the gene trap cassette (Fig. 1C)
Summary
Polycomb Group (PcG) proteins and their antagonists, trithorax Group (trxG) proteins, were identified in Drosophila as transcriptional repressors and activators of homeotic genes (Hox genes), respectively [1,2,3]. Mutations in PcG and trxG genes disrupt the specification of anterior-posterior (A/P) positional information and lead to homeotic transformations. In addition to their roles in A/P patterning, PcG and trxG proteins are involved in many developmental processes and diseases [4,5,6,7]. Polycomb-group (PcG) and trithorax-group (trxG) proteins regulate histone methylation to establish repressive and active chromatin configurations at target loci, respectively. These chromatin configurations are passed on from mother to daughter cells, thereby causing heritable changes in gene expression. In order to understand the functions of mammalian Asx-like (Asxl) proteins, we generated an Asxl mutant mouse from a gene-trap ES cell line
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