Structural elements promote architectural stripe formation and facilitate ultra-long-range gene regulation at a human disease locus.

Chen, Liang-Fu; Long, Hannah Katherine; Park, Minhee; Swigut, Tomek; Boettiger, Alistair Nicol; Wysocka, Joanna

Chen, Liang-Fu; Long, Hannah Katherine; Park, Minhee; Swigut, Tomek; Boettiger, Alistair Nicol; Wysocka, Joanna.

Afiliación

Chen LF; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Long HK; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Park M; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Swigut T; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Boettiger AN; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: boettiger@stanford.edu.
Wysocka J; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of M

Mol Cell ; 83(9): 1446-1461.e6, 2023 05 04.

Article en En | MEDLINE | ID: mdl-36996812

RESUMEN

Enhancer clusters overlapping disease-associated mutations in Pierre Robin sequence (PRS) patients regulate SOX9 expression at genomic distances over 1.25 Mb. We applied optical reconstruction of chromatin architecture (ORCA) imaging to trace 3D locus topology during PRS-enhancer activation. We observed pronounced changes in locus topology between cell types. Subsequent analysis of single-chromatin fiber traces revealed that these ensemble-average differences arise through changes in the frequency of commonly sampled topologies. We further identified two CTCF-bound elements, internal to the SOX9 topologically associating domain, which promote stripe formation, are positioned near the domain's 3D geometric center, and bridge enhancer-promoter contacts in a series of chromatin loops. Ablation of these elements results in diminished SOX9 expression and altered domain-wide contacts. Polymer models with uniform loading across the domain and frequent cohesin collisions recapitulate this multi-loop, centrally clustered geometry. Together, we provide mechanistic insights into architectural stripe formation and gene regulation over ultra-long genomic ranges.

Asunto(s)

Cromatina; Secuencias Reguladoras de Ácidos Nucleicos; Humanos; Cromatina/genética; Regiones Promotoras Genéticas; Regulación de la Expresión Génica; Genoma; Proteínas de Ciclo Celular/metabolismo; Elementos de Facilitación Genéticos; Factor de Unión a CCCTC/genética; Factor de Unión a CCCTC/metabolismo

Palabras clave

3D genome architecture; CTCF; enhancer; gene regulation; loop extrusion; stripe-associated structural element

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cromatina / Secuencias Reguladoras de Ácidos Nucleicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google