An expansive human regulatory lexicon encoded in transcription factor footprints.
Nature
; 489(7414): 83-90, 2012 Sep 06.
Article
en En
| MEDLINE
| ID: mdl-22955618
ABSTRACT
Regulatory factor binding to genomic DNA protects the underlying sequence from cleavage by DNase I, leaving nucleotide-resolution footprints. Using genomic DNase I footprinting across 41 diverse cell and tissue types, we detected 45 million transcription factor occupancy events within regulatory regions, representing differential binding to 8.4 million distinct short sequence elements. Here we show that this small genomic sequence compartment, roughly twice the size of the exome, encodes an expansive repertoire of conserved recognition sequences for DNA-binding proteins that nearly doubles the size of the human cis-regulatory lexicon. We find that genetic variants affecting allelic chromatin states are concentrated in footprints, and that these elements are preferentially sheltered from DNA methylation. High-resolution DNase I cleavage patterns mirror nucleotide-level evolutionary conservation and track the crystallographic topography of protein-DNA interfaces, indicating that transcription factor structure has been evolutionarily imprinted on the human genome sequence. We identify a stereotyped 50-base-pair footprint that precisely defines the site of transcript origination within thousands of human promoters. Finally, we describe a large collection of novel regulatory factor recognition motifs that are highly conserved in both sequence and function, and exhibit cell-selective occupancy patterns that closely parallel major regulators of development, differentiation and pluripotency.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
ADN
/
Genoma Humano
/
Secuencias Reguladoras de Ácidos Nucleicos
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Huella de ADN
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Enciclopedias como Asunto
/
Anotación de Secuencia Molecular
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Nature
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos