Epigenetic Reprogramming of Lineage-Committed Human Mammary Epithelial Cells Requires DNMT3A and Loss of DOT1L

Autor: Jerrica L. Breindel, Adam Skibinski, Maja Sedic, Ania Wronski-Campos, Wenhui Zhou, Patricia J. Keller, Joslyn Mills, James Bradner, Tamer Onder, Charlotte Kuperwasser
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: Stem Cell Reports, Vol 9, Iss 3, Pp 943-955 (2017)
Druh dokumentu: article
ISSN: 2213-6711
DOI: 10.1016/j.stemcr.2017.06.019
Popis: Organogenesis and tissue development occur through sequential stepwise processes leading to increased lineage restriction and loss of pluripotency. An exception to this appears in the adult human breast, where rare variant epithelial cells exhibit pluripotency and multilineage differentiation potential when removed from the signals of their native microenvironment. This phenomenon provides a unique opportunity to study mechanisms that lead to cellular reprogramming and lineage plasticity in real time. Here, we show that primary human mammary epithelial cells (HMECs) lose expression of differentiated mammary epithelial markers in a manner dependent on paracrine factors and epigenetic regulation. Furthermore, we demonstrate that HMEC reprogramming is dependent on gene silencing by the DNA methyltransferase DNMT3A and loss of histone transcriptional marks following downregulation of the methyltransferase DOT1L. These results demonstrate that lineage commitment in adult tissues is context dependent and highlight the plasticity of somatic cells when removed from their native tissue microenvironment.
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