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Association of cohesin and Nipped-B with transcriptionally active regions of the Drosophila melanogaster genome

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Abstract

The cohesin complex is a chromosomal component required for sister chromatid cohesion that is conserved from yeast to man. The similarly conserved Nipped-B protein is needed for cohesin to bind to chromosomes. In higher organisms, Nipped-B and cohesin regulate gene expression and development by unknown mechanisms. Using chromatin immunoprecipitation, we find that Nipped-B and cohesin bind to the same sites throughout the entire non-repetitive Drosophila genome. They preferentially bind transcribed regions and overlap with RNA polymerase II. This contrasts sharply with yeast, where cohesin binds almost exclusively between genes. Differences in cohesin and Nipped-B binding between Drosophila cell lines often correlate with differences in gene expression. For example, cohesin and Nipped-B bind the Abd-B homeobox gene in cells in which it is transcribed, but not in cells in which it is silenced. They bind to the Abd-B transcription unit and downstream regulatory region and thus could regulate both transcriptional elongation and activation. We posit that transcription facilitates cohesin binding, perhaps by unfolding chromatin, and that Nipped-B then regulates gene expression by controlling cohesin dynamics. These mechanisms are likely involved in the etiology of Cornelia de Lange syndrome, in which mutation of one copy of the NIPBL gene encoding the human Nipped-B ortholog causes diverse structural and mental birth defects.

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Acknowledgment

The authors thank Cheri van de Bunte and Joel Eissenberg for comments on the manuscript and Jumin Zhou for helpful discussions. Kc167 and ML-DmBG3 cells were obtained from the Drosophila Genomics Resource Center at Indiana University. This work was supported by NIH grants R01GM055683 (DD), R01GM070444 (MDB), P01HD052860 (DD, Project III Director; Ian Krantz, PI), and March of Dimes FY05-103 (DD). Work at Lawrence Berkeley National Laboratory was performed under Department of Energy contract DE-AC02-05CH11231. The microarray CEL files have been deposited with the NCBI GEO database under accession no. GSE9248. Processed ChIP data files are available upon request.

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Authors and Affiliations

  1. Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA

    Ziva Misulovin, Maria Gause & Dale Dorsett

  2. Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ, 08854, USA

    Yuri B. Schwartz, Tatyana G. Kahn & Vincenzo Pirrotta

  3. Berkeley Drosophila Transcription Network Project, Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA

    Xiao-Yong Li, Stewart MacArthur, Michael B. Eisen & Mark D. Biggin

  4. Department of Genetics, Washington University School of Medicine, Saint Louis, MO, 63108, USA

    Justin C. Fay

  5. Center for Integrative Genomics, Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA

    Michael B. Eisen

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  1. Ziva Misulovin
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Communicated by F. Uhlmann

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Supplementary Table 1

Genes that bind cohesin within annotated transcription units (DOC 648 KB)

Supplementary Fig. 1

Binding of Nipped-B and cohesin to transcribed genes. The top panel shows the binding of RNA polymerase II (PolII), Nipped-B and cohesin subunits to the expressed Act5c actin gene in Sg4, Kc, and ML-DmBG3 (BG3) cells. The bottom shows the binding of PolII, Nipped-B, and cohesin to the Kr-h1 gene in Sg4 cells and lack of binding to the same gene in BG3 cells. The Sg4 tracks are in black, the Kc track is red, and the BG3 tracks are blue. The trimmed mean log2 IP/control values are plotted on a scale of −0.5 to 3.0, except for the Sg4 PolII track, which is on a scale of −0.5 to 3.5 (GIF 65 KB).

High resolution image file (TIF 9.82 MB).

Supplementary Fig. 2

Nipped-B and cohesin bind preferentially to 5′ UTRs and introns. The plots compare the positions of predicted Nipped-B and SA peaks to annotated Drosophila genome features (Berkeley Drosophila Genome Project, April 2004 release; Celniker et al. 2002). Nipped-B and SA peaks predicted with a 25% false discovery rate using the TiMAT program are taken in rank order starting with the most significant from left to right in sliding windows of 500 peaks. For each window, the fraction of peaks that are in intergenic sequences, introns, coding sequences, and 3′ and 5′ UTRs are calculated. The color-coded straight lines labeled on the right show the fraction of the non-repetitive genome that corresponds to each genome feature. These data show that the largest fraction of the highest-ranked SA and Nipped-B peaks are in introns, followed by intergenic, 5′ UTR, coding, and 3′ UTR sequences. Relative to the fraction of the genome, SA cohesin and Nipped-B binding sites are most over-represented in 5′ UTRs, followed by introns, and are most under-represented in coding sequences, followed by 3′ UTRs and intergenic sequences (see Table 2). The top half of the peaks was used to calculate the binding preference ratios in Table 2 (GIF 65 KB).

High resolution image file (TIF 11.3 MB).

Supplementary Fig. 3

Nipped-B and cohesin binding peaks at transcription start sites. The average enrichment for Nipped-B and the SA cohesin subunit for microarray features is plotted for all genes that overlap cohesin binding regions in Sg4 cells from 10 kb upstream of the transcription start site (−10,000 bp) to 10 kb downstream of the transcription start site (10,000 bp) The IP to control ratios for all the microarray features in 500-bp windows were averaged. On average, both Nipped-B and SA enrichment are highest around the transcription start site, which is consistent with the high frequency of Nipped-B and cohesin peaks in 5′ UTRs (Supplementary Fig. 2). There is also a slight skewing towards the transcribed region, which is consistent with the slight preference of cohesin for introns seen in Supplementary Fig. 2, but does not explain the low occurrence of cohesin peaks in coding sequences (GIF 21.1 KB).

High resolution image file (TIF 4.16 MB).

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Misulovin, Z., Schwartz, Y.B., Li, XY. et al. Association of cohesin and Nipped-B with transcriptionally active regions of the Drosophila melanogaster genome. Chromosoma 117, 89–102 (2008). https://doi.org/10.1007/s00412-007-0129-1

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