title: Enhancer activation requires trans-recruitment of a mega transcription factor complex.
abstract: Enhancers provide critical information directing cell-type-specific transcriptional programs, regulated by binding of signal-dependent transcription factors and their associated cofactors. Here, we report that the most strongly activated estrogen (E2)-responsive enhancers are characterized by trans-recruitment and in situ assembly of a large 1-2 MDa complex of diverse DNA-binding transcription factors by ERα at ERE-containing enhancers. We refer to enhancers recruiting these factors as mega transcription factor-bound in trans (MegaTrans) enhancers. The MegaTrans complex is a signature of the most potent functional enhancers and is required for activation of enhancer RNA transcription and recruitment of coactivators, including p300 and Med1. The MegaTrans complex functions, in part, by recruiting specific enzymatic machinery, exemplified by DNA-dependent protein kinase. Thus, MegaTrans-containing enhancers represent a cohort of functional enhancers that mediate a broad and important transcriptional program and provide a molecular explanation for transcription factor clustering and hotspots noted in the genome.
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: z9liu@ucsd.edu.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Graduate Program in Bioinformatics and System Biology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Merkurjev
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Li
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Graduate Program in Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Soohwan
authors.initials: S
authors.lastname: Oh
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Meyer J
authors.initials: MJ
authors.lastname: Friedman
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; CAS Key Laboratory of Brain Function and Disease and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Song
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Graduate Program in Bioinformatics and System Biology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Ohgi
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Krones
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: mrosenfeld@ucsd.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
mesh_terms: D004742:Enhancer Elements, Genetic; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; C496499:FOXA1 protein, human; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D046912:Multiprotein Complexes; D014157:Transcription Factors