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CAGE-defined promoter regions of the genes implicated in Rett Syndrome.

Vitezic M, Bertin N, Andersson R, Lipovich L, Kawaji H, Lassmann T, Sandelin A, Heutink P, Goldowitz D, Ha T, Zhang P, Patrizi A, Fagiolini M, Forrest AR, Carninci P, Saxena A, FANTOM Consorti - BMC Genomics (2014)

Bottom Line: We show that FOXG1 expression is poorly correlated with the expression of MECP2 and CDKL5.We identify promoter shapes for each TSS, the predicted location of enhancers for each gene and the common transcription factors likely to regulate the three genes.Our data imply Polycomb Repressive Complex 2 (PRC2) mediated silencing of Foxg1 in cerebellum.

View Article: PubMed Central - PubMed

Affiliation: Omics Science Center, RIKEN Yokohama Institute, Omics Science Center (OSC), 1-17-22 Suehiro cho, Tsurumi ku, Yokohama, Japan. mvitezic@gmail.com.

ABSTRACT

Background: Mutations in three functionally diverse genes cause Rett Syndrome. Although the functions of Forkhead box G1 (FOXG1), Methyl CpG binding protein 2 (MECP2) and Cyclin-dependent kinase-like 5 (CDKL5) have been studied individually, not much is known about their relation to each other with respect to expression levels and regulatory regions. Here we analyzed data from hundreds of mouse and human samples included in the FANTOM5 project, to identify transcript initiation sites, expression levels, expression correlations and regulatory regions of the three genes.

Results: Our investigations reveal the predominantly used transcription start sites (TSSs) for each gene including novel transcription start sites for FOXG1. We show that FOXG1 expression is poorly correlated with the expression of MECP2 and CDKL5. We identify promoter shapes for each TSS, the predicted location of enhancers for each gene and the common transcription factors likely to regulate the three genes. Our data imply Polycomb Repressive Complex 2 (PRC2) mediated silencing of Foxg1 in cerebellum.

Conclusions: Our analyses provide a comprehensive picture of the regulatory regions of the three genes involved in Rett Syndrome.

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Related in: MedlinePlus

Shapes of key promoters of the three genes. Promoter shapes were drawn for the key promoters of the three genes (panels a to j, as labeled) based on the location of the first nucleotide in all tissues in mouse (panels a to e) and humans (panels f to j). Shape conservation is seen across the two species in all promoters except pB of Foxg1 in mouse and p2 of FOXG1 in humans. Despite the closeness in location and high correlation between p1 and p2 of CDKL5, we find variation in their shapes suggesting differential regulation in both species.
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Fig5: Shapes of key promoters of the three genes. Promoter shapes were drawn for the key promoters of the three genes (panels a to j, as labeled) based on the location of the first nucleotide in all tissues in mouse (panels a to e) and humans (panels f to j). Shape conservation is seen across the two species in all promoters except pB of Foxg1 in mouse and p2 of FOXG1 in humans. Despite the closeness in location and high correlation between p1 and p2 of CDKL5, we find variation in their shapes suggesting differential regulation in both species.

Mentions: It is known that promoters regulated by TATA boxes are ‘sharp’ where transcript initiation occurs at a well defined dominant site, no more than 4 consecutive nucleotides long, while promoters regulated by CpG islands are ‘broad’ where multiple start sites can be detected in a broad genomic region [48]. We analyzed the extracted TSSs for sharp or broad shapes by aligning their expression levels across the genomic locus. For our investigation, we defined sharp promoters as those where the majority of the transcripts start from a single dominant TSS or from multiple TSSs within 5 nucleotides, while promoters were classified as broad when they had multiple dominating initiation sites within a defined TSS cluster (maximum 50 bp genomic window). We analyzed in humans and mouse, the 3 main promoters for FOXG1 and two promoters each for MECP2 and CDKL5. Our analyses revealed that the main promoters for FOXG1 in both species (p1@FOXG1 and pA@Foxg1) were broad in keeping with the CpG islands in their vicinity (Figure 5a, 5f). The second highest expressed FOXG1 promoters in human and mouse (p2@FOXG1 and pB@Foxg1) appeared to have species-specific shapes and regulation. While p2@FOXG1 in humans was found to be sharp with no TATA-box or CpG island, pB@Foxg1 in mouse was broad and CpG regulated (Figure 5b, 5g). In each species we found for FOXG1, one sharp promoter (p3@FOXG1 and p1@foxg1) devoid of TATA box or CpG island (Additional file 15: Figures S9a,f).Figure 5


CAGE-defined promoter regions of the genes implicated in Rett Syndrome.

Vitezic M, Bertin N, Andersson R, Lipovich L, Kawaji H, Lassmann T, Sandelin A, Heutink P, Goldowitz D, Ha T, Zhang P, Patrizi A, Fagiolini M, Forrest AR, Carninci P, Saxena A, FANTOM Consorti - BMC Genomics (2014)

Shapes of key promoters of the three genes. Promoter shapes were drawn for the key promoters of the three genes (panels a to j, as labeled) based on the location of the first nucleotide in all tissues in mouse (panels a to e) and humans (panels f to j). Shape conservation is seen across the two species in all promoters except pB of Foxg1 in mouse and p2 of FOXG1 in humans. Despite the closeness in location and high correlation between p1 and p2 of CDKL5, we find variation in their shapes suggesting differential regulation in both species.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4522966&req=5

Fig5: Shapes of key promoters of the three genes. Promoter shapes were drawn for the key promoters of the three genes (panels a to j, as labeled) based on the location of the first nucleotide in all tissues in mouse (panels a to e) and humans (panels f to j). Shape conservation is seen across the two species in all promoters except pB of Foxg1 in mouse and p2 of FOXG1 in humans. Despite the closeness in location and high correlation between p1 and p2 of CDKL5, we find variation in their shapes suggesting differential regulation in both species.
Mentions: It is known that promoters regulated by TATA boxes are ‘sharp’ where transcript initiation occurs at a well defined dominant site, no more than 4 consecutive nucleotides long, while promoters regulated by CpG islands are ‘broad’ where multiple start sites can be detected in a broad genomic region [48]. We analyzed the extracted TSSs for sharp or broad shapes by aligning their expression levels across the genomic locus. For our investigation, we defined sharp promoters as those where the majority of the transcripts start from a single dominant TSS or from multiple TSSs within 5 nucleotides, while promoters were classified as broad when they had multiple dominating initiation sites within a defined TSS cluster (maximum 50 bp genomic window). We analyzed in humans and mouse, the 3 main promoters for FOXG1 and two promoters each for MECP2 and CDKL5. Our analyses revealed that the main promoters for FOXG1 in both species (p1@FOXG1 and pA@Foxg1) were broad in keeping with the CpG islands in their vicinity (Figure 5a, 5f). The second highest expressed FOXG1 promoters in human and mouse (p2@FOXG1 and pB@Foxg1) appeared to have species-specific shapes and regulation. While p2@FOXG1 in humans was found to be sharp with no TATA-box or CpG island, pB@Foxg1 in mouse was broad and CpG regulated (Figure 5b, 5g). In each species we found for FOXG1, one sharp promoter (p3@FOXG1 and p1@foxg1) devoid of TATA box or CpG island (Additional file 15: Figures S9a,f).Figure 5

Bottom Line: We show that FOXG1 expression is poorly correlated with the expression of MECP2 and CDKL5.We identify promoter shapes for each TSS, the predicted location of enhancers for each gene and the common transcription factors likely to regulate the three genes.Our data imply Polycomb Repressive Complex 2 (PRC2) mediated silencing of Foxg1 in cerebellum.

View Article: PubMed Central - PubMed

Affiliation: Omics Science Center, RIKEN Yokohama Institute, Omics Science Center (OSC), 1-17-22 Suehiro cho, Tsurumi ku, Yokohama, Japan. mvitezic@gmail.com.

ABSTRACT

Background: Mutations in three functionally diverse genes cause Rett Syndrome. Although the functions of Forkhead box G1 (FOXG1), Methyl CpG binding protein 2 (MECP2) and Cyclin-dependent kinase-like 5 (CDKL5) have been studied individually, not much is known about their relation to each other with respect to expression levels and regulatory regions. Here we analyzed data from hundreds of mouse and human samples included in the FANTOM5 project, to identify transcript initiation sites, expression levels, expression correlations and regulatory regions of the three genes.

Results: Our investigations reveal the predominantly used transcription start sites (TSSs) for each gene including novel transcription start sites for FOXG1. We show that FOXG1 expression is poorly correlated with the expression of MECP2 and CDKL5. We identify promoter shapes for each TSS, the predicted location of enhancers for each gene and the common transcription factors likely to regulate the three genes. Our data imply Polycomb Repressive Complex 2 (PRC2) mediated silencing of Foxg1 in cerebellum.

Conclusions: Our analyses provide a comprehensive picture of the regulatory regions of the three genes involved in Rett Syndrome.

Show MeSH
Related in: MedlinePlus