Co-motif discovery identifies an Esrrb-Sox2-DNA ternary complex as a mediator of transcriptional differences between mouse embryonic and epiblast stem cells
Transcription factors (TF) often bind in heterodimeric complexes with each TF recognizing a specific neighboring cis element in the regulatory region of the genome. Comprehension of this DNA motif grammar is opaque, yet recent developments have allowed the interrogation of genome-wide TF binding sit...
| Main Authors: | , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2014
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| Online Access: | https://hdl.handle.net/10356/102237 http://hdl.handle.net/10220/18922 |
| _version_ | 1826119740081307648 |
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| author | Mistri, Tapan Kumar Rahmani, Mehran Woon, Chow Thai Ng, Calista Keow Leng Jauch, Ralf Robson, Paul Hutchins, Andrew Paul Choo, Siew Hua |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Mistri, Tapan Kumar Rahmani, Mehran Woon, Chow Thai Ng, Calista Keow Leng Jauch, Ralf Robson, Paul Hutchins, Andrew Paul Choo, Siew Hua |
| author_sort | Mistri, Tapan Kumar |
| collection | NTU |
| description | Transcription factors (TF) often bind in heterodimeric complexes with each TF recognizing a specific neighboring cis element in the regulatory region of the genome. Comprehension of this DNA motif grammar is opaque, yet recent developments have allowed the interrogation of genome-wide TF binding sites. We reasoned that within this data novel motif grammars could be identified that controlled distinct biological programs. For this purpose, we developed a novel motif-discovery tool termed fexcom that systematically interrogates ChIP-seq data to discover spatially constrained TF–TF composite motifs occurring over short DNA distances. We applied this to the extensive ChIP-seq data available from mouse embryonic stem cells (ESCs). In addition to the well-known and most prevalent sox-oct motif, we also discovered a novel constrained spacer motif for Esrrb and Sox2 with a gap of between 2 and 8 bps that Essrb and Sox2 cobind in a selective fashion. Through the use of knockdown experiments, we argue that the Esrrb-Sox2 complex is an arbiter of gene expression differences between ESCs and epiblast stem cells (EpiSC). A number of genes downregulated upon dual Esrrb/Sox2 knockdown (e.g., Klf4, Klf5, Jam2, Pecam1) are similarly downregulated in the ESC to EpiSC transition and contain the esrrb-sox motif. The prototypical Esrrb-Sox2 target gene, containing an esrrb-sox element conserved throughout eutherian and metatherian mammals, is Nr0b1. Through positive regulation of this transcriptional repressor, we argue the Esrrb-Sox2 complex promotes the ESC state through inhibition of the EpiSC transcriptional program and the same trio may also function to maintain trophoblast stem cells. |
| first_indexed | 2024-10-01T05:05:03Z |
| format | Journal Article |
| id | ntu-10356/102237 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:05:03Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | ntu-10356/1022372020-03-07T12:18:16Z Co-motif discovery identifies an Esrrb-Sox2-DNA ternary complex as a mediator of transcriptional differences between mouse embryonic and epiblast stem cells Mistri, Tapan Kumar Rahmani, Mehran Woon, Chow Thai Ng, Calista Keow Leng Jauch, Ralf Robson, Paul Hutchins, Andrew Paul Choo, Siew Hua School of Biological Sciences DRNTU::Science::Biological sciences::Cytology Transcription factors (TF) often bind in heterodimeric complexes with each TF recognizing a specific neighboring cis element in the regulatory region of the genome. Comprehension of this DNA motif grammar is opaque, yet recent developments have allowed the interrogation of genome-wide TF binding sites. We reasoned that within this data novel motif grammars could be identified that controlled distinct biological programs. For this purpose, we developed a novel motif-discovery tool termed fexcom that systematically interrogates ChIP-seq data to discover spatially constrained TF–TF composite motifs occurring over short DNA distances. We applied this to the extensive ChIP-seq data available from mouse embryonic stem cells (ESCs). In addition to the well-known and most prevalent sox-oct motif, we also discovered a novel constrained spacer motif for Esrrb and Sox2 with a gap of between 2 and 8 bps that Essrb and Sox2 cobind in a selective fashion. Through the use of knockdown experiments, we argue that the Esrrb-Sox2 complex is an arbiter of gene expression differences between ESCs and epiblast stem cells (EpiSC). A number of genes downregulated upon dual Esrrb/Sox2 knockdown (e.g., Klf4, Klf5, Jam2, Pecam1) are similarly downregulated in the ESC to EpiSC transition and contain the esrrb-sox motif. The prototypical Esrrb-Sox2 target gene, containing an esrrb-sox element conserved throughout eutherian and metatherian mammals, is Nr0b1. Through positive regulation of this transcriptional repressor, we argue the Esrrb-Sox2 complex promotes the ESC state through inhibition of the EpiSC transcriptional program and the same trio may also function to maintain trophoblast stem cells. 2014-03-20T08:15:52Z 2019-12-06T20:52:06Z 2014-03-20T08:15:52Z 2019-12-06T20:52:06Z 2012 2012 Journal Article Hutchins, A. P., Choo, S. H., Mistri, T. K., Rahmani, M., Woon, C. T., Ng, C. K. L., et al. (2013). Co-motif discovery identifies an Esrrb-Sox2-DNA ternary complex as a mediator of transcriptional differences between mouse embryonic and epiblast stem cells. Stem cells, 31(2), 269-281. 1066-5099 https://hdl.handle.net/10356/102237 http://hdl.handle.net/10220/18922 10.1002/stem.1279 en Stem cells © 2012 AlphaMed Press. |
| spellingShingle | DRNTU::Science::Biological sciences::Cytology Mistri, Tapan Kumar Rahmani, Mehran Woon, Chow Thai Ng, Calista Keow Leng Jauch, Ralf Robson, Paul Hutchins, Andrew Paul Choo, Siew Hua Co-motif discovery identifies an Esrrb-Sox2-DNA ternary complex as a mediator of transcriptional differences between mouse embryonic and epiblast stem cells |
| title | Co-motif discovery identifies an Esrrb-Sox2-DNA ternary complex as a mediator of transcriptional differences between mouse embryonic and epiblast stem cells |
| title_full | Co-motif discovery identifies an Esrrb-Sox2-DNA ternary complex as a mediator of transcriptional differences between mouse embryonic and epiblast stem cells |
| title_fullStr | Co-motif discovery identifies an Esrrb-Sox2-DNA ternary complex as a mediator of transcriptional differences between mouse embryonic and epiblast stem cells |
| title_full_unstemmed | Co-motif discovery identifies an Esrrb-Sox2-DNA ternary complex as a mediator of transcriptional differences between mouse embryonic and epiblast stem cells |
| title_short | Co-motif discovery identifies an Esrrb-Sox2-DNA ternary complex as a mediator of transcriptional differences between mouse embryonic and epiblast stem cells |
| title_sort | co motif discovery identifies an esrrb sox2 dna ternary complex as a mediator of transcriptional differences between mouse embryonic and epiblast stem cells |
| topic | DRNTU::Science::Biological sciences::Cytology |
| url | https://hdl.handle.net/10356/102237 http://hdl.handle.net/10220/18922 |
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