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Sequential activation of genetic programs in mouse mammary epithelium during pregnancy depends on STAT5A/B concentration

The transcription factors Signal Transducer and Activator of Transcription (STAT) 5A/B mediate prolactin-induced mammary development during pregnancy. However, it is not clear how the different processes, expansion and maturation of alveolar precursor cells and the differential induction of milk pro...

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Autores principales: Yamaji, Daisuke, Kang, Keunsoo, Robinson, Gertraud W., Hennighausen, Lothar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561979/
https://www.ncbi.nlm.nih.gov/pubmed/23275557
http://dx.doi.org/10.1093/nar/gks1310
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author Yamaji, Daisuke
Kang, Keunsoo
Robinson, Gertraud W.
Hennighausen, Lothar
author_facet Yamaji, Daisuke
Kang, Keunsoo
Robinson, Gertraud W.
Hennighausen, Lothar
author_sort Yamaji, Daisuke
collection PubMed
description The transcription factors Signal Transducer and Activator of Transcription (STAT) 5A/B mediate prolactin-induced mammary development during pregnancy. However, it is not clear how the different processes, expansion and maturation of alveolar precursor cells and the differential induction of milk protein genes are regulated on a molecular level. We have used mouse genetics and genome-wide analyses to determine how altering concentrations of STAT5A and STAT5B impacts mammary epithelial development during pregnancy and the regulation of target genes. The presence of only a single Stat5a or Stat5b allele was sufficient for the establishment of histologically undifferentiated alveolar units and two alleles permitted the execution of a differentiation program similar to that found with all four alleles. While one copy of Stat5 induced limited expression of target genes, two copies activated a lactation-like gene signature. Using ChIP-seq analyses on intact tissue under physiological conditions, we found that highly expressed and regulated genes were bound by STAT5 in their promoter proximal regions, whereas upstream binding had minor biological consequences. Remarkably, 80% of the genes bound by STAT5 in vivo were not under STAT5 control. RNA polymerase II intensity was directly proportional to STAT5 concentration only on STAT5 regulated genes providing mechanistic insight by which STAT5 activates mammary specific genes.
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spelling pubmed-35619792013-02-01 Sequential activation of genetic programs in mouse mammary epithelium during pregnancy depends on STAT5A/B concentration Yamaji, Daisuke Kang, Keunsoo Robinson, Gertraud W. Hennighausen, Lothar Nucleic Acids Res Gene Regulation, Chromatin and Epigenetics The transcription factors Signal Transducer and Activator of Transcription (STAT) 5A/B mediate prolactin-induced mammary development during pregnancy. However, it is not clear how the different processes, expansion and maturation of alveolar precursor cells and the differential induction of milk protein genes are regulated on a molecular level. We have used mouse genetics and genome-wide analyses to determine how altering concentrations of STAT5A and STAT5B impacts mammary epithelial development during pregnancy and the regulation of target genes. The presence of only a single Stat5a or Stat5b allele was sufficient for the establishment of histologically undifferentiated alveolar units and two alleles permitted the execution of a differentiation program similar to that found with all four alleles. While one copy of Stat5 induced limited expression of target genes, two copies activated a lactation-like gene signature. Using ChIP-seq analyses on intact tissue under physiological conditions, we found that highly expressed and regulated genes were bound by STAT5 in their promoter proximal regions, whereas upstream binding had minor biological consequences. Remarkably, 80% of the genes bound by STAT5 in vivo were not under STAT5 control. RNA polymerase II intensity was directly proportional to STAT5 concentration only on STAT5 regulated genes providing mechanistic insight by which STAT5 activates mammary specific genes. Oxford University Press 2013-02 2012-12-26 /pmc/articles/PMC3561979/ /pubmed/23275557 http://dx.doi.org/10.1093/nar/gks1310 Text en Published by Oxford University Press 2012. http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial reuse, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.
spellingShingle Gene Regulation, Chromatin and Epigenetics
Yamaji, Daisuke
Kang, Keunsoo
Robinson, Gertraud W.
Hennighausen, Lothar
Sequential activation of genetic programs in mouse mammary epithelium during pregnancy depends on STAT5A/B concentration
title Sequential activation of genetic programs in mouse mammary epithelium during pregnancy depends on STAT5A/B concentration
title_full Sequential activation of genetic programs in mouse mammary epithelium during pregnancy depends on STAT5A/B concentration
title_fullStr Sequential activation of genetic programs in mouse mammary epithelium during pregnancy depends on STAT5A/B concentration
title_full_unstemmed Sequential activation of genetic programs in mouse mammary epithelium during pregnancy depends on STAT5A/B concentration
title_short Sequential activation of genetic programs in mouse mammary epithelium during pregnancy depends on STAT5A/B concentration
title_sort sequential activation of genetic programs in mouse mammary epithelium during pregnancy depends on stat5a/b concentration
topic Gene Regulation, Chromatin and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561979/
https://www.ncbi.nlm.nih.gov/pubmed/23275557
http://dx.doi.org/10.1093/nar/gks1310
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