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  Human Lineage-Specific Transcriptional Regulation through GA-Binding Protein Transcription Factor Alpha (GABPa)

Perdomo-Sabogal, A., Nowick, K., Piccini, I., Sudbrak, R., Lehrach, H., Yaspo, M. L., et al. (2016). Human Lineage-Specific Transcriptional Regulation through GA-Binding Protein Transcription Factor Alpha (GABPa). Molecular Biology and Evolution, 33(5), 1231-1244. doi:10.1093/molbev/msw007.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-B7F6-C Version Permalink: http://hdl.handle.net/21.11116/0000-0000-B7F7-B
Genre: Journal Article

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 Creators:
Perdomo-Sabogal, A., Author
Nowick, K., Author
Piccini, I., Author
Sudbrak, R., Author
Lehrach, H.1, Author              
Yaspo, M. L.2, Author              
Warnatz, H. J.2, Author              
Querfurth, R., Author
Affiliations:
1Emeritus Group of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385697              
2Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2117287              

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Free keywords: Animals Binding Sites Biological Evolution COS Cells Cercopithecus aethiops Chromatin Immunoprecipitation Chromosome Mapping Evolution, Molecular GA-Binding Protein Transcription Factor/*genetics/*metabolism *Gene Expression Regulation Genetic Speciation HEK293 Cells Humans Promoter Regions, Genetic Protein Binding Sequence Alignment Zinc Fingers/genetics *ChIP-Seq *Gabp *KRAB zinc finger genes *comparative genomics. *human molecular evolution *human-specific binding sites *promoter assay
 Abstract: A substantial fraction of phenotypic differences between closely related species are likely caused by differences in gene regulation. While this has already been postulated over 30 years ago, only few examples of evolutionary changes in gene regulation have been verified. Here, we identified and investigated binding sites of the transcription factor GA-binding protein alpha (GABPa) aiming to discover cis-regulatory adaptations on the human lineage. By performing chromatin immunoprecipitation-sequencing experiments in a human cell line, we found 11,619 putative GABPa binding sites. Through sequence comparisons of the human GABPa binding regions with orthologous sequences from 34 mammals, we identified substitutions that have resulted in 224 putative human-specific GABPa binding sites. To experimentally assess the transcriptional impact of those substitutions, we selected four promoters for promoter-reporter gene assays using human and African green monkey cells. We compared the activities of wild-type promoters to mutated forms, where we have introduced one or more substitutions to mimic the ancestral state devoid of the GABPa consensus binding sequence. Similarly, we introduced the human-specific substitutions into chimpanzee and macaque promoter backgrounds. Our results demonstrate that the identified substitutions are functional, both in human and nonhuman promoters. In addition, we performed GABPa knock-down experiments and found 1,215 genes as strong candidates for primary targets. Further analyses of our data sets link GABPa to cognitive disorders, diabetes, KRAB zinc finger (KRAB-ZNF), and human-specific genes. Thus, we propose that differences in GABPa binding sites played important roles in the evolution of human-specific phenotypes.

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Language(s): eng - English
 Dates: 2016-01-262016
 Publication Status: Published in print
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1093/molbev/msw007
ISSN: 1537-1719 (Electronic)0737-4038 (Print)
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Title: Molecular Biology and Evolution
  Other : Mol. Biol. Evol.
Source Genre: Journal
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Publ. Info: Oxford : Oxford University Press
Pages: - Volume / Issue: 33 (5) Sequence Number: - Start / End Page: 1231 - 1244 Identifier: ISSN: 0737-4038
CoNE: /journals/resource/954925536119