193
GRNs Controlling Xenopus Embryogenesis
shown to affect the expression of linked genes (Pomerantz
et al., 2009; Musunuru et al., 2010). This raises the possibility that SNPs within CRMs are causes of many human
genetic diseases and phenotypic traits. Recent genome-wide
studies examining DNase I hypersensitive sites harboring
GWAS SNPs showed enrichment of SNPs in regulatory
regions, supporting the involvement of cis regulatory DNA
variations in human diseases (Maurano et al., 2012). This
study also revealed that common variants associated with
specifc diseases (e.g., infammation, cancer, diabetes) are
often enriched in defned sets of TF motifs, indicating that
cohorts of TFs form shared GRN architectures and that
alterations in TF binding to these sites cause these diseases.
Thus, seemingly unconnected SNPs may be associated with
related diseases, perhaps by altering TF activity that affects
common GRNs. In sum, we anticipate that GRN study will
contribute broadly to understanding the etiology of human
health and disease.
REFERENCES
Afouda, B.A., Y. Nakamura, S. Shaw, R.M. Charney, K.D.
Paraiso, I.L. Blitz, K.W.Y. Cho, and Hoppler, S. 2020.
Foxh1/nodal def nes context-specifc direct maternal Wnt/
β-Catenin target gene regulation in early development.
iScience 23:101314.
Alon, U. 2007. Network motifs: Theory and experimental approaches.
Nat Rev Genet 8:450–461.
Artinger, M., I. Blitz, K. Inoue, U. Tran, and K.W. Cho. 1997.
Interaction of goosecoid and brachyury in Xenopus mesoderm patterning. Mech Dev 65:187–196.
Bardet, A.F., J. Steinmann, S. Bafna, J.A. Knoblich, J. Zeitlinger,
and A. Stark. 2013. Identifcation of transcription factor binding sites from ChIP-seq data at high resolution.
Bioinformatics 29:2705–2713.
Blitz, I.L., J. Biesinger, X. Xie, and K.W.Y. Cho. 2013. Biallelic
genome modifcation in F0 Xenopus tropicalis embryos
using the CRISPR/Cas system. Genesis 51:827–834.
Blitz, I.L., and K.W.Y. Cho. 2021. Control of zygotic genome activation in Xenopus. Curr Top Dev Biol 145, in press.
Blitz, I.L., K.D. Paraiso, I. Patrushev, W.T. Chiu, K.W.Y. Cho, and
M.J. Gilchrist. 2017. A catalog of Xenopus tropicalis transcription factors and their regional expression in the early
gastrula stage embryo. Dev Biol 426:409–417.
Brannon, M., M. Gomperts, L. Sumoy, R.T, Moon, and D.
Kimelman. 1997. A beta-catenin/XTcf-3 complex binds to
the siamois promoter to regulate dorsal axis specif cation in
Xenopus. Genes Dev 11:2359–2370.
Brickman, J.M., C.M. Jones, M. Clements, J.C. Smith., and R.S.P.
Beddington. 2000. Hex is a transcriptional repressor that
contributes to anterior identity and suppresses Spemann
organiser function. Development 127:2303–2315.
Briggs, J.A., C. Weinreb, D.E. Wagner, S. Megason, L. Peshkin,
M.W. Kirschner, and A.M. Klein. 2018. The dynamics of
gene expression in vertebrate embryogenesis at single-cell
resolution. Science 360:6392.
Britten, R.J., and E.H. Davidson. 1969. Gene regulation for higher
cells: A theory. Science 165:349–357.
Cha, S.W., M. McAdams, J. Kormish, C.C. Wylie, and M. Kofron.
2012. Foxi2 is an animally localized maternal mRNA in
Xenopus, and an activator of the zygotic ectoderm activator
Foxi1e. PLoS One 7:e41782.
Charney, R.M., E. Forouzmand, J.S. Cho, J. Cheung, K.D. Paraiso,
Y. Yasuoka, S. Takahashi, M. Taira, I.L. Blitz, X. Xie, and
K.W.Y. Cho. 2017b. Foxh1 occupies cis-regulatory modules
prior to dynamic transcription factor interactions controlling
the mesendoderm gene program. Dev Cell 40:595–607.
Charney, R.M., K.D. Paraiso, I.L. Blitz, and K.W.Y. Cho. 2017a. A
gene regulatory program controlling early Xenopus mesendoderm formation: Network conservation and motifs. Semin
Cell Dev Biol 66:12–24.
Chiu, W.T., R. Charney Le, I.L. Blitz, M.B. Fish, Y. Li, J. Biesinger,
X. Xie, and K.W.Y. Cho. 2014. Genome-wide view of TGF/
Foxh1 regulation of the early mesendoderm program.
Development 141:4537–4547.
Ciau-Uitz, A., and R. Patient. 2019. Gene regulatory networks governing the generation and regeneration of blood. Journal of
Computational Biology 26:719–725.
Davidson, E.H. 2006. The Regulatory Genome: Gene Regulatory
Networks in Development and Evolution. Academic Press,
San Diego, CA.
Faure, E., I.S. Peter, and E.H. Davidson. 2012. A new software
package for predictive gene regulatory network modeling
and redesign. J Comput Biol 20:419–423.
Forouzmand, E., N.D.L. Owens, I.L. Blitz, K.D. Paraiso, M.K.
Khokha, M.J. Gilchrist, X. Xie, and K.W.Y. Cho. 2017.
Developmentally regulated long non-coding RNAs in
Xenopus tropicalis. Dev Biol 426:401–408.
Gentsch, G.E., T. Spruce, N.D.L. Owens, and J.C. Smith. 2019.
Maternal pluripotency factors initiate extensive chromatin
remodelling to predef ne frst response to inductive signals.
Nat Commun 10:4269.
Gray, S., P. Szymanski, and M. Levine. 1994. Short-range repression permits multiple enhancers to function autonomously
within a complex promoter. Genes Dev 8:1829–1838.
Green, J., and J.C. Smith. 1990. Graded changes in dose of a
Xenopus activin a homologue elicit stepwise transitions in
embryonic cell fate. Nature 347:391–394.
Guo, X., T. Zhang, Z. Hu, Y. Zhang, Z. Shi, Q. Wang, Y. Cui,
F. Wang, H. Zhao, Y. Chen. 2014. Eff cient RNA/Cas9mediated genome editing in Xenopus tropicalis. Development
141:707–714.
Harland, R. 2000. Neural induction. Curr Opin Genet Dev 10:
357–362.
Hawley, S.H., K Wünnenberg-Stapleton, C. Hashimoto, M.N.
Laurent, T. Watabe, B.W. Blumberg, and K.W. Cho. 1995.
Disruption of BMP signals in embryonic Xenopus ectoderm
leads to direct neural induction. Genes Dev 9:2923–2935.
Henningfeld, K.A., H. Friedle, S. Rastegar, and W. Knöchel.
2002. Autoregulation of Xvent-2B; direct interaction and
functional cooperation of Xvent-2 and Smad1. J Biol Chem
277:2097–2103.
Jansen, C., R.N. Ramirez, N.C. El-Ali, D. Gomez-Cabrero, J.
Tegner, M. Merkenschlager, A. Conesa, and A. Mortazavi.
2019. Building gene regulatory networks from scATAC-seq
and scRNA-seq using linked self organizing maps. PLoS
Comput Biol 15:e1006555.
Jansen, C., K.D. Paraiso, J.J. Zhou, I.L., Blitz, M.B. Fish, R.M.
Charney, J.S. Cho, Y. Yasuoka, N. Sudou, S.R. Bright, M. Wlizla,
G.J.C Veenstra, M. Taira, A.M. Zorn, A. Mortazavi, and K.W.Y.
Cho. 2022. Uncovering the mesendoderm gene regulatory network through multi-omic data integration. Cell Rep. 38:110364.
BioRxiv. https://doi: 10.1016/j.celrep.2022.110364.
Kiang, M.Y., and A. Kumar. 2001. An evaluation of self-organizing
map networks as a robust alternative to factor analysis in
data mining applications. Information Systems Research
12:177–194.
GRNs Controlling Xenopus Embryogenesis
shown to affect the expression of linked genes (Pomerantz
et al., 2009; Musunuru et al., 2010). This raises the possibility that SNPs within CRMs are causes of many human
genetic diseases and phenotypic traits. Recent genome-wide
studies examining DNase I hypersensitive sites harboring
GWAS SNPs showed enrichment of SNPs in regulatory
regions, supporting the involvement of cis regulatory DNA
variations in human diseases (Maurano et al., 2012). This
study also revealed that common variants associated with
specifc diseases (e.g., infammation, cancer, diabetes) are
often enriched in defned sets of TF motifs, indicating that
cohorts of TFs form shared GRN architectures and that
alterations in TF binding to these sites cause these diseases.
Thus, seemingly unconnected SNPs may be associated with
related diseases, perhaps by altering TF activity that affects
common GRNs. In sum, we anticipate that GRN study will
contribute broadly to understanding the etiology of human
health and disease.
REFERENCES
Afouda, B.A., Y. Nakamura, S. Shaw, R.M. Charney, K.D.
Paraiso, I.L. Blitz, K.W.Y. Cho, and Hoppler, S. 2020.
Foxh1/nodal def nes context-specifc direct maternal Wnt/
β-Catenin target gene regulation in early development.
iScience 23:101314.
Alon, U. 2007. Network motifs: Theory and experimental approaches.
Nat Rev Genet 8:450–461.
Artinger, M., I. Blitz, K. Inoue, U. Tran, and K.W. Cho. 1997.
Interaction of goosecoid and brachyury in Xenopus mesoderm patterning. Mech Dev 65:187–196.
Bardet, A.F., J. Steinmann, S. Bafna, J.A. Knoblich, J. Zeitlinger,
and A. Stark. 2013. Identifcation of transcription factor binding sites from ChIP-seq data at high resolution.
Bioinformatics 29:2705–2713.
Blitz, I.L., J. Biesinger, X. Xie, and K.W.Y. Cho. 2013. Biallelic
genome modifcation in F0 Xenopus tropicalis embryos
using the CRISPR/Cas system. Genesis 51:827–834.
Blitz, I.L., and K.W.Y. Cho. 2021. Control of zygotic genome activation in Xenopus. Curr Top Dev Biol 145, in press.
Blitz, I.L., K.D. Paraiso, I. Patrushev, W.T. Chiu, K.W.Y. Cho, and
M.J. Gilchrist. 2017. A catalog of Xenopus tropicalis transcription factors and their regional expression in the early
gastrula stage embryo. Dev Biol 426:409–417.
Brannon, M., M. Gomperts, L. Sumoy, R.T, Moon, and D.
Kimelman. 1997. A beta-catenin/XTcf-3 complex binds to
the siamois promoter to regulate dorsal axis specif cation in
Xenopus. Genes Dev 11:2359–2370.
Brickman, J.M., C.M. Jones, M. Clements, J.C. Smith., and R.S.P.
Beddington. 2000. Hex is a transcriptional repressor that
contributes to anterior identity and suppresses Spemann
organiser function. Development 127:2303–2315.
Briggs, J.A., C. Weinreb, D.E. Wagner, S. Megason, L. Peshkin,
M.W. Kirschner, and A.M. Klein. 2018. The dynamics of
gene expression in vertebrate embryogenesis at single-cell
resolution. Science 360:6392.
Britten, R.J., and E.H. Davidson. 1969. Gene regulation for higher
cells: A theory. Science 165:349–357.
Cha, S.W., M. McAdams, J. Kormish, C.C. Wylie, and M. Kofron.
2012. Foxi2 is an animally localized maternal mRNA in
Xenopus, and an activator of the zygotic ectoderm activator
Foxi1e. PLoS One 7:e41782.
Charney, R.M., E. Forouzmand, J.S. Cho, J. Cheung, K.D. Paraiso,
Y. Yasuoka, S. Takahashi, M. Taira, I.L. Blitz, X. Xie, and
K.W.Y. Cho. 2017b. Foxh1 occupies cis-regulatory modules
prior to dynamic transcription factor interactions controlling
the mesendoderm gene program. Dev Cell 40:595–607.
Charney, R.M., K.D. Paraiso, I.L. Blitz, and K.W.Y. Cho. 2017a. A
gene regulatory program controlling early Xenopus mesendoderm formation: Network conservation and motifs. Semin
Cell Dev Biol 66:12–24.
Chiu, W.T., R. Charney Le, I.L. Blitz, M.B. Fish, Y. Li, J. Biesinger,
X. Xie, and K.W.Y. Cho. 2014. Genome-wide view of TGF/
Foxh1 regulation of the early mesendoderm program.
Development 141:4537–4547.
Ciau-Uitz, A., and R. Patient. 2019. Gene regulatory networks governing the generation and regeneration of blood. Journal of
Computational Biology 26:719–725.
Davidson, E.H. 2006. The Regulatory Genome: Gene Regulatory
Networks in Development and Evolution. Academic Press,
San Diego, CA.
Faure, E., I.S. Peter, and E.H. Davidson. 2012. A new software
package for predictive gene regulatory network modeling
and redesign. J Comput Biol 20:419–423.
Forouzmand, E., N.D.L. Owens, I.L. Blitz, K.D. Paraiso, M.K.
Khokha, M.J. Gilchrist, X. Xie, and K.W.Y. Cho. 2017.
Developmentally regulated long non-coding RNAs in
Xenopus tropicalis. Dev Biol 426:401–408.
Gentsch, G.E., T. Spruce, N.D.L. Owens, and J.C. Smith. 2019.
Maternal pluripotency factors initiate extensive chromatin
remodelling to predef ne frst response to inductive signals.
Nat Commun 10:4269.
Gray, S., P. Szymanski, and M. Levine. 1994. Short-range repression permits multiple enhancers to function autonomously
within a complex promoter. Genes Dev 8:1829–1838.
Green, J., and J.C. Smith. 1990. Graded changes in dose of a
Xenopus activin a homologue elicit stepwise transitions in
embryonic cell fate. Nature 347:391–394.
Guo, X., T. Zhang, Z. Hu, Y. Zhang, Z. Shi, Q. Wang, Y. Cui,
F. Wang, H. Zhao, Y. Chen. 2014. Eff cient RNA/Cas9mediated genome editing in Xenopus tropicalis. Development
141:707–714.
Harland, R. 2000. Neural induction. Curr Opin Genet Dev 10:
357–362.
Hawley, S.H., K Wünnenberg-Stapleton, C. Hashimoto, M.N.
Laurent, T. Watabe, B.W. Blumberg, and K.W. Cho. 1995.
Disruption of BMP signals in embryonic Xenopus ectoderm
leads to direct neural induction. Genes Dev 9:2923–2935.
Henningfeld, K.A., H. Friedle, S. Rastegar, and W. Knöchel.
2002. Autoregulation of Xvent-2B; direct interaction and
functional cooperation of Xvent-2 and Smad1. J Biol Chem
277:2097–2103.
Jansen, C., R.N. Ramirez, N.C. El-Ali, D. Gomez-Cabrero, J.
Tegner, M. Merkenschlager, A. Conesa, and A. Mortazavi.
2019. Building gene regulatory networks from scATAC-seq
and scRNA-seq using linked self organizing maps. PLoS
Comput Biol 15:e1006555.
Jansen, C., K.D. Paraiso, J.J. Zhou, I.L., Blitz, M.B. Fish, R.M.
Charney, J.S. Cho, Y. Yasuoka, N. Sudou, S.R. Bright, M. Wlizla,
G.J.C Veenstra, M. Taira, A.M. Zorn, A. Mortazavi, and K.W.Y.
Cho. 2022. Uncovering the mesendoderm gene regulatory network through multi-omic data integration. Cell Rep. 38:110364.
BioRxiv. https://doi: 10.1016/j.celrep.2022.110364.
Kiang, M.Y., and A. Kumar. 2001. An evaluation of self-organizing
map networks as a robust alternative to factor analysis in
data mining applications. Information Systems Research
12:177–194.