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. 2008 Oct 17;322(5900):434-8.
doi: 10.1126/science.1160930. Epub 2008 Sep 11.

Species-specific transcription in mice carrying human chromosome 21

Michael D Wilson  1 , Nuno L Barbosa-Morais, Dominic Schmidt, Caitlin M Conboy, Lesley Vanes, Victor L J Tybulewicz, Elizabeth M C Fisher, Simon Tavaré, Duncan T Odom
Affiliations

Species-specific transcription in mice carrying human chromosome 21

Michael D Wilson et al. Science. .

Abstract

Homologous sets of transcription factors direct conserved tissue-specific gene expression, yet transcription factor-binding events diverge rapidly between closely related species. We used hepatocytes from an aneuploid mouse strain carrying human chromosome 21 to determine, on a chromosomal scale, whether interspecies differences in transcriptional regulation are primarily directed by human genetic sequence or mouse nuclear environment. Virtually all transcription factor-binding locations, landmarks of transcription initiation, and the resulting gene expression observed in human hepatocytes were recapitulated across the entire human chromosome 21 in the mouse hepatocyte nucleus. Thus, in homologous tissues, genetic sequence is largely responsible for directing transcriptional programs; interspecies differences in epigenetic machinery, cellular environment, and transcription factors themselves play secondary roles.

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Figures

Figure 1
Figure 1
Transcriptional regulation varies between human and mouse hepatocytes across a complete chromosome. (A) Genome track showing chromatin immunoprecipitation enrichment of HNF1α binding in wild-type mouse and human hepatocytes across 30 kb of genomic sequence. The species of bound DNA sequences and ChIP signal is indicated by color: purple represents human, orange represents mouse. Highlighted in green are HNF1α-bound regions that are shared by both species, human-unique, and mouse-unique. (B) The total number of genomic regions occupied by three transcription factors (HNF1α, HNF4α, and HNF6) and the trimethylated form of histone H3K4 (H3K4me3) that are shared between the species, human-unique, or mouse-unique. ChIP data was obtained in wild-type mouse and human hepatocytes across the homologous regions of human chromosome 21 and mouse chromosome 16.
Figure 2
Figure 2
Comparison of the binding of the liver-specific transcription factors HNF1α, HNF4α, and HNF6, and enrichment of H3K4me3 on TcHsChr21 with the corresponding data obtained in mouse TcMmChr16 and human WtHsChr21 regions. The color scheme is the same as in Fig 1; notably, the primary difference from Fig 1 is the addition of the human chromosome in a mouse environment, which is indicated as a purple bar (representing the human chromosomal sequences) with an orange peak (from mouse transcription factor binding). The binding events on TcHsChr21 are sorted into categories based on whether they align with similar peaks in mouse and human (shared), align only with peaks in human (cis-directed), or align only with peaks in mice (trans-directed).
Figure 3
Figure 3
Patterns of transcription factor binding and transcription initiation are determined by genetic sequence. ChIP enrichment for (A) HNF1α, (B) HNF4α, (C) HNF6, and (D) H3K4me3 are shown across a 50 kb surrounding the liver-expressed gene CLDN14. The human chromosome 21 coordinates, and the vertebrate sequence conservation track (Seq Cons; genome.ucsc.edu) are shown flanking CLDN14. Each panel shows the species of genetic sequence as a bar colored by species (human: purple, mouse: orange) below a track showing ChIP enrichment, similarly colored by species.
Figure 4
Figure 4
Gene expression in the Tc1 mouse originating from the mouse and human chromosomes is largely indistinguishable from comparable wild-type nuclear environments. Volcano plots (empirical Bayes log odds of differential expression versus average log fold change) demonstrating that (A) Tc1 hepatocytes have high transcription occurring from the transplanted human chromosome 21 using human genomic arrays and wild-type littermate mRNA as a reference (black probes map to human genes; blue probes map to genes located on HsChr21; red probes map to regions absent from TcHsChr21); whereas (B) wild-type and Tc1 mouse gene expression on mouse genomic arrays have indistinguishable patterns of transcription (black probes map to mouse genes). (C) Plot of the log expression of TcHsChr21 (y-axis) transcripts versus WtHsChr21 (x-axis) transcripts (Rcorr ≈ 0.90). (D) Plot of the log expression of TcHsChr21 (y-axis) transcripts versus WtMmChr16 (x-axis) orthologous transcripts (Rcorr ≈ 0.28).
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Comment in

  • Genetics. It's the sequence, stupid!
    Coller HA, Kruglyak L. Coller HA, et al. Science. 2008 Oct 17;322(5900):380-1. doi: 10.1126/science.1165664. Science. 2008. PMID: 18927376 Free PMC article. No abstract available.

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