FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription.
Complex organisms require tissue-specific transcriptional programs, yet little is known about how these are established. The transcription factor FoxA1 is thought to contribute to gene regulation through its ability to act as a pioneer factor binding to nucleosomal DNA. Through genome-wide positional analyses, we demonstrate that FoxA1 cell type-specific functions rely primarily on differential recruitment to chromatin predominantly at distant enhancers rather than proximal promoters. This differential recruitment leads to cell type-specific changes in chromatin structure and functional collaboration with lineage-specific transcription factors. Despite the ability of FoxA1 to bind nucleosomes, its differential binding to chromatin sites is dependent on the distribution of histone H3 lysine 4 dimethylation. Together, our results suggest that methylation of histone H3 lysine 4 is part of the epigenetic signature that defines lineage-specific FoxA1 recruitment sites in chromatin. FoxA1 translates this epigenetic signature into changes in chromatin structure thereby establishing lineage-specific transcriptional enhancers and programs.
Lupien
Mathieu
M
Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Eeckhoute
Jérôme
J
Meyer
Clifford A
CA
Wang
Qianben
Q
Zhang
Yong
Y
Li
Wei
W
Carroll
Jason S
JS
Liu
X Shirley
XS
Brown
Myles
M
D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D015894:Genome, Human; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism*; D042421:Histone Code; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D011944:Receptors, Androgen / Q000378:metabolism; D014158:Transcription, Genetic
D047628:Estrogen Receptor alpha; D004967:Estrogens; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; D011944:Receptors, Androgen