CCAAT Promoter element regulates transgenerational expression of the MHC class I gene.

Weissman, Jocelyn D; Kotekar, Aparna; Barbash, Zohar; Mu, Jie; Singer, Dinah S

Weissman, Jocelyn D; Kotekar, Aparna; Barbash, Zohar; Mu, Jie; Singer, Dinah S.

Afiliación

Weissman JD; Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bldg 10, Room 4B-36, Bethesda, MD, 20892, USA.
Kotekar A; NIH Center for Human Immunology, Inflammation, and Autoimmunity (CHI), National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
Barbash Z; FORE Biotherapeutics, Philadelphia, PA, USA.
Mu J; Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bldg 10, Room 4B-36, Bethesda, MD, 20892, USA.
Singer DS; Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bldg 10, Room 4B-36, Bethesda, MD, 20892, USA. Dinah.Singer@nih.gov.

Chromosoma ; 133(3): 203-216, 2024 Jul.

Article en En | MEDLINE | ID: mdl-38922437

ABSTRACT

ABSTRACT

Transgenerational gene expression depends on both underlying DNA sequences and epigenetic modifications. The latter, which can result in transmission of variegated gene expression patterns across multiple generations without DNA alterations, has been termed epigenetic inheritance and has been documented in plants, worms, flies and mammals. Whereas transcription factors binding to cognate DNA sequence elements regulate gene expression, the molecular basis for epigenetic inheritance has been linked to histone and DNA modifications and non-coding RNA. Here we report that mutation of the CCAAT box promoter element abrogates NF-Y binding and disrupts the stable transgenerational expression of an MHC class I transgene. Transgenic mice with a mutated CCAAT box in the MHC class I transgene display variegated expression of the transgene among littermates and progeny in multiple independently derived transgenic lines. After 4 generations, CCAAT mutant transgenic lines derived from a single founder stably displayed distinct patterns of expression. Histone modifications and RNA polymerase II binding correlate with expression of CCAAT mutant transgenic lines, whereas DNA methylation and nucleosome occupancy do not. Mutation of the CCAAT box also results in changes to CTCF binding and DNA looping patterns across the transgene that correlate with expression status. These studies identify the CCAAT promoter element as a regulator of stable transgenerational gene expression such that mutation of the CCAAT box results in variegated transgenerational inheritance. Considering that the CCAAT box is present in 30% of eukaryotic promoters, this study provides insights into how fidelity of gene expression patterns is maintained through multiple generations.

Asunto(s)

Ratones Transgénicos; Regiones Promotoras Genéticas; Animales; Ratones; Metilación de ADN; Epigénesis Genética; Factor de Unión a CCAAT/genética; Factor de Unión a CCAAT/metabolismo; Regulación de la Expresión Génica; Genes MHC Clase I; Mutación; Histonas/metabolismo; Histonas/genética; ARN Polimerasa II/metabolismo; ARN Polimerasa II/genética; Factor de Unión a CCCTC/metabolismo; Factor de Unión a CCCTC/genética; Transgenes; Nucleosomas/metabolismo; Nucleosomas/genética

Palabras clave

CCAAT box; Epigenetic modifications; MHC class I gene; Promoter element; Transgenerational inheritance

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: Ratones Transgénicos / Regiones Promotoras Genéticas Límite: Animals Idioma: En Revista: Chromosoma Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Austria

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google