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2. Gata2, Fli1, and Scl form a recursively wired gene-regulatory circuit during early hematopoietic development

Author

Pimanda, John E., Ottersbach, Katrin, Knezevic, Kathy, Kinston, Sarah, Chan, Wan Y.I., Wilson, Nicola K., Landry, Josette-Renee, Wood, Andrew D., Kolb-Kokocinski, Anja, Green, Anthony R., Tannahill, David, Lacaud, Georges, Kouskoff, Valerie, and Gottgens, Berthold

Subjects
Hematopoietic system -- Genetic aspects, Hematopoietic stem cells -- Properties, DNA binding proteins -- Properties, Science and technology
Abstract

Conservation of the vertebrate body plan has been attributed to the evolutionary stability of gene-regulatory networks (GRNs). We describe a regulatory circuit made up of Gata2, Fli1, and Scl/Tal1 and their enhancers, Gata2-3, Fli1+12, and Sci+19, that operates during specification of hematopoiesis in the mouse embryo. We show that the Fli1+12 enhancer, like the Gata2-3 and Sci + 19 enhancers, targets hematopoietic stem cells (HSCs) and relies on a combination of Ets, Gata, and E-Box motifs. We show that the Gata2-3 enhancer also uses a similar cluster of motifs and that Gata2, Fli1, and Scl are expressed in embryonic day-11.5 dorsal aorta where HSCs originate and in fetal liver where they multiply. The three HSC enhancers in these tissues and in ES cell-derived hemangioblast equivalents are bound by each of these transcription factors (TFs) and form a fully connected triad that constitutes a previously undescribed example of both this network motif in mammalian development and a GRN kernel operating during the specification of a mammalian stem cell. hemangioblast | hematopoiesis | hematopoietic stem cell | network motif | transcription factor network

Published
2007

3. Genome-wide association study to identify genetic determinants of severe asthma

Author

Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, and Hall, Ian P.

Abstract

Background The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear.Objective To identify common genetic variants affecting susceptibility to severe asthma.Methods A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies.Results An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10(−8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10(−8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance.Conclusions The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

Published
2012

4. The paralogous hematopoietic regulators Lyl1and Sclare coregulated by Ets and GATA factors, but Lyl1cannot rescue the early Scl–/–phenotype

Author

Chan, Wan Y.I., Follows, George A., Lacaud, Georges, Pimanda, John E., Landry, Josette-Renee, Kinston, Sarah, Knezevic, Kathy, Piltz, Sandie, Donaldson, Ian J., Gambardella, Laure, Sablitzky, Fred, Green, Anthony R., Kouskoff, Valerie, and Göttgens, Berthold

Abstract

Transcription factors are key regulators of hematopoietic stem cells (HSCs), yet the molecular mechanisms that control their expression are largely unknown. Previously, we demonstrated that expression of Scl/Tal1, a transcription factor required for the specification of HSCs, is controlled by Ets and GATA factors. Here we characterize the molecular mechanisms controlling expression of Lyl1, a paralog of Sclalso required for HSC function. Two closely spaced promoters directed expression to hematopoietic progenitor, megakaryocytic, and endothelial cells in transgenic mice. Conserved binding sites required for promoter activity were bound in vivo by GATA-2 and the Ets factors Fli1, Elf1, Erg, and PU.1. However, despite coregulation of Scland Lyl1by the same Ets and GATA factors, Sclexpression was initiated prior to Lyl1in embryonic stem (ES) cell differentiation assays. Moreover, ectopic expression of Sclbut not Lyl1rescued hematopoietic differentiation in Scl−/−ES cells, thus providing a molecular explanation for the vastly different phenotypes of Scl−/−and Lyl1−/−mouse embryos. Furthermore, coregulation of Scland Lyl1later during development may explain the mild phenotype of Scl−/−adult HSCs.

Published
2007
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5. Genome-wide association study to identify genetic determinants of severe asthma

Author

Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, Hall, Ian P., Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, and Hall, Ian P.

Abstract

Background The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective To identify common genetic variants affecting susceptibility to severe asthma. Methods A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10(−8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10(−8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

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6. Genome-wide association study to identify genetic determinants of severe asthma

Author

Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, Hall, Ian P., Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, and Hall, Ian P.

Abstract

Background The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective To identify common genetic variants affecting susceptibility to severe asthma. Methods A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10(−8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10(−8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

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7. Genome-wide association study to identify genetic determinants of severe asthma

Author

Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, Hall, Ian P., Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, and Hall, Ian P.

Abstract

Background The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective To identify common genetic variants affecting susceptibility to severe asthma. Methods A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10(−8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10(−8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

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8. Genome-wide association study to identify genetic determinants of severe asthma

Author

Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, Hall, Ian P., Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, and Hall, Ian P.

Abstract

Background The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective To identify common genetic variants affecting susceptibility to severe asthma. Methods A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10(−8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10(−8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

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9. Genome-wide association study to identify genetic determinants of severe asthma

Author

Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, Hall, Ian P., Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, and Hall, Ian P.

Abstract

Background The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective To identify common genetic variants affecting susceptibility to severe asthma. Methods A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10(−8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10(−8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

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