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Systematic Identification of cis-Regulatory Sequences Active in Mouse and Human Embryonic Stem Cells

Understanding the transcriptional regulation of pluripotent cells is of fundamental interest and will greatly inform efforts aimed at directing differentiation of embryonic stem (ES) cells or reprogramming somatic cells. We first analyzed the transcriptional profiles of mouse ES cells and primordial...

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Autores principales: Grskovic, Marica, Chaivorapol, Christina, Gaspar-Maia, Alexandre, Li, Hao, Ramalho-Santos, Miguel
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959362/
https://www.ncbi.nlm.nih.gov/pubmed/17784790
http://dx.doi.org/10.1371/journal.pgen.0030145
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author Grskovic, Marica
Chaivorapol, Christina
Gaspar-Maia, Alexandre
Li, Hao
Ramalho-Santos, Miguel
author_facet Grskovic, Marica
Chaivorapol, Christina
Gaspar-Maia, Alexandre
Li, Hao
Ramalho-Santos, Miguel
author_sort Grskovic, Marica
collection PubMed
description Understanding the transcriptional regulation of pluripotent cells is of fundamental interest and will greatly inform efforts aimed at directing differentiation of embryonic stem (ES) cells or reprogramming somatic cells. We first analyzed the transcriptional profiles of mouse ES cells and primordial germ cells and identified genes upregulated in pluripotent cells both in vitro and in vivo. These genes are enriched for roles in transcription, chromatin remodeling, cell cycle, and DNA repair. We developed a novel computational algorithm, CompMoby, which combines analyses of sequences both aligned and non-aligned between different genomes with a probabilistic segmentation model to systematically predict short DNA motifs that regulate gene expression. CompMoby was used to identify conserved overrepresented motifs in genes upregulated in pluripotent cells. We show that the motifs are preferentially active in undifferentiated mouse ES and embryonic germ cells in a sequence-specific manner, and that they can act as enhancers in the context of an endogenous promoter. Importantly, the activity of the motifs is conserved in human ES cells. We further show that the transcription factor NF-Y specifically binds to one of the motifs, is differentially expressed during ES cell differentiation, and is required for ES cell proliferation. This study provides novel insights into the transcriptional regulatory networks of pluripotent cells. Our results suggest that this systematic approach can be broadly applied to understanding transcriptional networks in mammalian species.
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spelling pubmed-19593622007-08-30 Systematic Identification of cis-Regulatory Sequences Active in Mouse and Human Embryonic Stem Cells Grskovic, Marica Chaivorapol, Christina Gaspar-Maia, Alexandre Li, Hao Ramalho-Santos, Miguel PLoS Genet Research Article Understanding the transcriptional regulation of pluripotent cells is of fundamental interest and will greatly inform efforts aimed at directing differentiation of embryonic stem (ES) cells or reprogramming somatic cells. We first analyzed the transcriptional profiles of mouse ES cells and primordial germ cells and identified genes upregulated in pluripotent cells both in vitro and in vivo. These genes are enriched for roles in transcription, chromatin remodeling, cell cycle, and DNA repair. We developed a novel computational algorithm, CompMoby, which combines analyses of sequences both aligned and non-aligned between different genomes with a probabilistic segmentation model to systematically predict short DNA motifs that regulate gene expression. CompMoby was used to identify conserved overrepresented motifs in genes upregulated in pluripotent cells. We show that the motifs are preferentially active in undifferentiated mouse ES and embryonic germ cells in a sequence-specific manner, and that they can act as enhancers in the context of an endogenous promoter. Importantly, the activity of the motifs is conserved in human ES cells. We further show that the transcription factor NF-Y specifically binds to one of the motifs, is differentially expressed during ES cell differentiation, and is required for ES cell proliferation. This study provides novel insights into the transcriptional regulatory networks of pluripotent cells. Our results suggest that this systematic approach can be broadly applied to understanding transcriptional networks in mammalian species. Public Library of Science 2007-08 2007-08-31 /pmc/articles/PMC1959362/ /pubmed/17784790 http://dx.doi.org/10.1371/journal.pgen.0030145 Text en © 2007 Grskovic et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Grskovic, Marica
Chaivorapol, Christina
Gaspar-Maia, Alexandre
Li, Hao
Ramalho-Santos, Miguel
Systematic Identification of cis-Regulatory Sequences Active in Mouse and Human Embryonic Stem Cells
title Systematic Identification of cis-Regulatory Sequences Active in Mouse and Human Embryonic Stem Cells
title_full Systematic Identification of cis-Regulatory Sequences Active in Mouse and Human Embryonic Stem Cells
title_fullStr Systematic Identification of cis-Regulatory Sequences Active in Mouse and Human Embryonic Stem Cells
title_full_unstemmed Systematic Identification of cis-Regulatory Sequences Active in Mouse and Human Embryonic Stem Cells
title_short Systematic Identification of cis-Regulatory Sequences Active in Mouse and Human Embryonic Stem Cells
title_sort systematic identification of cis-regulatory sequences active in mouse and human embryonic stem cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959362/
https://www.ncbi.nlm.nih.gov/pubmed/17784790
http://dx.doi.org/10.1371/journal.pgen.0030145
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