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1.
PLoS One ; 8(9): e75030, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24086428

RESUMO

Even in genomes lacking operons, a gene's position in the genome influences its potential for expression. The mechanisms by which adjacent genes are co-expressed are still not completely understood. Using lactation and the mammary gland as a model system, we explore the hypothesis that chromatin state contributes to the co-regulation of gene neighborhoods. The mammary gland represents a unique evolutionary model, due to its recent appearance, in the context of vertebrate genomes. An understanding of how the mammary gland is regulated to produce milk is also of biomedical and agricultural importance for human lactation and dairying. Here, we integrate epigenomic and transcriptomic data to develop a comprehensive regulatory model. Neighborhoods of mammary-expressed genes were determined using expression data derived from pregnant and lactating mice and a neighborhood scoring tool, G-NEST. Regions of open and closed chromatin were identified by ChIP-Seq of histone modifications H3K36me3, H3K4me2, and H3K27me3 in the mouse mammary gland and liver tissue during lactation. We found that neighborhoods of genes in regions of uniquely active chromatin in the lactating mammary gland, compared with liver tissue, were extremely rare. Rather, genes in most neighborhoods were suppressed during lactation as reflected in their expression levels and their location in regions of silenced chromatin. Chromatin silencing was largely shared between the liver and mammary gland during lactation, and what distinguished the mammary gland was mainly a small tissue-specific repertoire of isolated, expressed genes. These findings suggest that an advantage of the neighborhood organization is in the collective repression of groups of genes via a shared mechanism of chromatin repression. Genes essential to the mammary gland's uniqueness are isolated from neighbors, and likely have less tolerance for variation in expression, properties they share with genes responsible for an organism's survival.


Assuntos
Epigênese Genética , Genes , Genômica , Glândulas Mamárias Animais/metabolismo , Leite/metabolismo , Transcriptoma/genética , Animais , Cromatina/metabolismo , Cromossomos de Mamíferos/genética , Feminino , Perfilação da Expressão Gênica , Inativação Gênica , Histonas/metabolismo , Humanos , Lactação/genética , Camundongos , Camundongos Endogâmicos ICR , Especificidade de Órgãos/genética , Gravidez , Transcrição Gênica
2.
PLoS One ; 8(1): e53270, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23301053

RESUMO

BACKGROUND: Unlike other tissues, development and differentiation of the mammary gland occur mostly after birth. The roles of systemic hormones and local growth factors important for this development and functional differentiation are well-studied. In other tissues, it has been shown that chromatin organization plays a key role in transcriptional regulation and underlies epigenetic regulation during development and differentiation. However, the role of chromatin organization in mammary gland development and differentiation is less well-defined. Here, we have studied the changes in chromatin organization at the milk protein gene loci (casein, whey acidic protein, and others) in the mouse mammary gland before and after functional differentiation. METHODOLOGY/PRINCIPAL FINDINGS: Distal regulatory elements within the casein gene cluster and whey acidic protein gene region have an open chromatin organization after pubertal development, while proximal promoters only gain open-chromatin marks during pregnancy in conjunction with the major induction of their expression. In contrast, other milk protein genes, such as alpha-lactalbumin, already have an open chromatin organization in the mature virgin gland. Changes in chromatin organization in the casein gene cluster region that are present after puberty persisted after lactation has ceased, while the changes which occurred during pregnancy at the gene promoters were not maintained. In general, mammary gland expressed genes and their regulatory elements exhibit developmental stage- and tissue-specific chromatin organization. CONCLUSIONS/SIGNIFICANCE: A progressive gain of epigenetic marks indicative of open/active chromatin on genes marking functional differentiation accompanies the development of the mammary gland. These results support a model in which a chromatin organization is established during pubertal development that is then poised to respond to the systemic hormonal signals of pregnancy and lactation to achieve the full functional capacity of the mammary gland.


Assuntos
Epigênese Genética , Regulação da Expressão Gênica no Desenvolvimento , Glândulas Mamárias Animais/embriologia , Proteínas do Leite/genética , Albuminas/metabolismo , Animais , Diferenciação Celular , Cromatina/metabolismo , Metilação de DNA , Feminino , Histonas/metabolismo , Lactação , Fígado/metabolismo , Glândulas Mamárias Animais/crescimento & desenvolvimento , Camundongos , Proteínas do Leite/metabolismo , Regiões Promotoras Genéticas
3.
J Biol Chem ; 284(34): 22815-24, 2009 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-19542223

RESUMO

Lactogenic hormone regulation of beta-casein gene expression in mammary epithelial cells provides an excellent model in which to study the mechanisms by which steroid and peptide hormone signaling control gene expression. Prolactin- and glucocorticoid-mediated induction of beta-casein gene expression involves two principal regulatory regions, a proximal promoter and a distal enhancer located in the mouse approximately -6 kb upstream of the transcription start site. Using a chromosome conformation capture assay and quantitative real time PCR, we demonstrate that a chromatin loop is created in conjunction with the recruitment of specific transcription factors and p300 in HC11 mammary epithelial cells. Stimulation with both prolactin and hydrocortisone is required for the induction of these long range interactions between the promoter and enhancer, and no DNA looping was observed in nontreated cells or cells treated with each of the hormones separately. The lactogenic hormone-induced interaction between the proximal promoter and distal enhancer was confirmed in hormone-treated primary three-dimensional mammary acini cultures. In addition, the developmental regulation of DNA looping between the beta-casein regulatory regions was observed in lactating but not in virgin mouse mammary glands. Furthermore, beta-casein mRNA induction and long range interactions between these regulatory regions were inhibited in a progestin-dependent manner following stimulation with prolactin and hydrocortisone in HC11 cells expressing human PR-B. Collectively, these data suggest that the communication between these regulatory regions with intervening DNA looping is a crucial step required to both create and maintain active chromatin domains and regulate transcription.


Assuntos
Caseínas/genética , Glucocorticoides/farmacologia , Histona Desacetilases/metabolismo , Prolactina/farmacologia , Fator de Transcrição STAT5/metabolismo , Fator de Transcrição YY1/metabolismo , Animais , Técnicas de Cultura de Células , Linhagem Celular , Células Cultivadas , Cromatina/genética , Cromatina/metabolismo , Imunoprecipitação da Cromatina , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/metabolismo , Camundongos , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos
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