Transcription factors bind thousands of active and inactive regions in the Drosophila blastoderm.
Identifying the genomic regions bound by sequence-specific regulatory factors is central both to deciphering the complex DNA cis-regulatory code that controls transcription in metazoans and to determining the range of genes that shape animal morphogenesis. We used whole-genome tiling arrays to map s...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2008-02-01
|
| Series: | PLoS Biology |
| Online Access: | http://europepmc.org/articles/PMC2235902?pdf=render |
| _version_ | 1818618132158218240 |
|---|---|
| author | Xiao-yong Li Stewart MacArthur Richard Bourgon David Nix Daniel A Pollard Venky N Iyer Aaron Hechmer Lisa Simirenko Mark Stapleton Cris L Luengo Hendriks Hou Cheng Chu Nobuo Ogawa William Inwood Victor Sementchenko Amy Beaton Richard Weiszmann Susan E Celniker David W Knowles Tom Gingeras Terence P Speed Michael B Eisen Mark D Biggin |
| author_facet | Xiao-yong Li Stewart MacArthur Richard Bourgon David Nix Daniel A Pollard Venky N Iyer Aaron Hechmer Lisa Simirenko Mark Stapleton Cris L Luengo Hendriks Hou Cheng Chu Nobuo Ogawa William Inwood Victor Sementchenko Amy Beaton Richard Weiszmann Susan E Celniker David W Knowles Tom Gingeras Terence P Speed Michael B Eisen Mark D Biggin |
| author_sort | Xiao-yong Li |
| collection | DOAJ |
| description | Identifying the genomic regions bound by sequence-specific regulatory factors is central both to deciphering the complex DNA cis-regulatory code that controls transcription in metazoans and to determining the range of genes that shape animal morphogenesis. We used whole-genome tiling arrays to map sequences bound in Drosophila melanogaster embryos by the six maternal and gap transcription factors that initiate anterior-posterior patterning. We find that these sequence-specific DNA binding proteins bind with quantitatively different specificities to highly overlapping sets of several thousand genomic regions in blastoderm embryos. Specific high- and moderate-affinity in vitro recognition sequences for each factor are enriched in bound regions. This enrichment, however, is not sufficient to explain the pattern of binding in vivo and varies in a context-dependent manner, demonstrating that higher-order rules must govern targeting of transcription factors. The more highly bound regions include all of the over 40 well-characterized enhancers known to respond to these factors as well as several hundred putative new cis-regulatory modules clustered near developmental regulators and other genes with patterned expression at this stage of embryogenesis. The new targets include most of the microRNAs (miRNAs) transcribed in the blastoderm, as well as all major zygotically transcribed dorsal-ventral patterning genes, whose expression we show to be quantitatively modulated by anterior-posterior factors. In addition to these highly bound regions, there are several thousand regions that are reproducibly bound at lower levels. However, these poorly bound regions are, collectively, far more distant from genes transcribed in the blastoderm than highly bound regions; are preferentially found in protein-coding sequences; and are less conserved than highly bound regions. Together these observations suggest that many of these poorly bound regions are not involved in early-embryonic transcriptional regulation, and a significant proportion may be nonfunctional. Surprisingly, for five of the six factors, their recognition sites are not unambiguously more constrained evolutionarily than the immediate flanking DNA, even in more highly bound and presumably functional regions, indicating that comparative DNA sequence analysis is limited in its ability to identify functional transcription factor targets. |
| first_indexed | 2024-12-16T17:16:43Z |
| format | Article |
| id | doaj.art-1c0cb54e3f884aad8d2824668852d428 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-16T17:16:43Z |
| publishDate | 2008-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-1c0cb54e3f884aad8d2824668852d4282022-12-21T22:23:16ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852008-02-0162e2710.1371/journal.pbio.0060027Transcription factors bind thousands of active and inactive regions in the Drosophila blastoderm.Xiao-yong LiStewart MacArthurRichard BourgonDavid NixDaniel A PollardVenky N IyerAaron HechmerLisa SimirenkoMark StapletonCris L Luengo HendriksHou Cheng ChuNobuo OgawaWilliam InwoodVictor SementchenkoAmy BeatonRichard WeiszmannSusan E CelnikerDavid W KnowlesTom GingerasTerence P SpeedMichael B EisenMark D BigginIdentifying the genomic regions bound by sequence-specific regulatory factors is central both to deciphering the complex DNA cis-regulatory code that controls transcription in metazoans and to determining the range of genes that shape animal morphogenesis. We used whole-genome tiling arrays to map sequences bound in Drosophila melanogaster embryos by the six maternal and gap transcription factors that initiate anterior-posterior patterning. We find that these sequence-specific DNA binding proteins bind with quantitatively different specificities to highly overlapping sets of several thousand genomic regions in blastoderm embryos. Specific high- and moderate-affinity in vitro recognition sequences for each factor are enriched in bound regions. This enrichment, however, is not sufficient to explain the pattern of binding in vivo and varies in a context-dependent manner, demonstrating that higher-order rules must govern targeting of transcription factors. The more highly bound regions include all of the over 40 well-characterized enhancers known to respond to these factors as well as several hundred putative new cis-regulatory modules clustered near developmental regulators and other genes with patterned expression at this stage of embryogenesis. The new targets include most of the microRNAs (miRNAs) transcribed in the blastoderm, as well as all major zygotically transcribed dorsal-ventral patterning genes, whose expression we show to be quantitatively modulated by anterior-posterior factors. In addition to these highly bound regions, there are several thousand regions that are reproducibly bound at lower levels. However, these poorly bound regions are, collectively, far more distant from genes transcribed in the blastoderm than highly bound regions; are preferentially found in protein-coding sequences; and are less conserved than highly bound regions. Together these observations suggest that many of these poorly bound regions are not involved in early-embryonic transcriptional regulation, and a significant proportion may be nonfunctional. Surprisingly, for five of the six factors, their recognition sites are not unambiguously more constrained evolutionarily than the immediate flanking DNA, even in more highly bound and presumably functional regions, indicating that comparative DNA sequence analysis is limited in its ability to identify functional transcription factor targets.http://europepmc.org/articles/PMC2235902?pdf=render |
| spellingShingle | Xiao-yong Li Stewart MacArthur Richard Bourgon David Nix Daniel A Pollard Venky N Iyer Aaron Hechmer Lisa Simirenko Mark Stapleton Cris L Luengo Hendriks Hou Cheng Chu Nobuo Ogawa William Inwood Victor Sementchenko Amy Beaton Richard Weiszmann Susan E Celniker David W Knowles Tom Gingeras Terence P Speed Michael B Eisen Mark D Biggin Transcription factors bind thousands of active and inactive regions in the Drosophila blastoderm. PLoS Biology |
| title | Transcription factors bind thousands of active and inactive regions in the Drosophila blastoderm. |
| title_full | Transcription factors bind thousands of active and inactive regions in the Drosophila blastoderm. |
| title_fullStr | Transcription factors bind thousands of active and inactive regions in the Drosophila blastoderm. |
| title_full_unstemmed | Transcription factors bind thousands of active and inactive regions in the Drosophila blastoderm. |
| title_short | Transcription factors bind thousands of active and inactive regions in the Drosophila blastoderm. |
| title_sort | transcription factors bind thousands of active and inactive regions in the drosophila blastoderm |
| url | http://europepmc.org/articles/PMC2235902?pdf=render |
| work_keys_str_mv | AT xiaoyongli transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT stewartmacarthur transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT richardbourgon transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT davidnix transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT danielapollard transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT venkyniyer transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT aaronhechmer transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT lisasimirenko transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT markstapleton transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT crislluengohendriks transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT houchengchu transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT nobuoogawa transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT williaminwood transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT victorsementchenko transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT amybeaton transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT richardweiszmann transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT susanecelniker transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT davidwknowles transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT tomgingeras transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT terencepspeed transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT michaelbeisen transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm AT markdbiggin transcriptionfactorsbindthousandsofactiveandinactiveregionsinthedrosophilablastoderm |