title: MEF2D drives photoreceptor development through a genome-wide competition for tissue-specific enhancers.
abstract: Organismal development requires the precise coordination of genetic programs to regulate cell fate and function. MEF2 transcription factors (TFs) play essential roles in this process but how these broadly expressed factors contribute to the generation of specific cell types during development is poorly understood. Here we show that despite being expressed in virtually all mammalian tissues, in the retina MEF2D binds to retina-specific enhancers and controls photoreceptor cell development. MEF2D achieves specificity by cooperating with a retina-specific factor CRX, which recruits MEF2D away from canonical MEF2 binding sites and redirects it to retina-specific enhancers that lack the consensus MEF2-binding sequence. Once bound to retina-specific enhancers, MEF2D and CRX co-activate the expression of photoreceptor-specific genes that are critical for retinal function. These findings demonstrate that broadly expressed TFs acquire specific functions through competitive recruitment to enhancers by tissue-specific TFs and through selective activation of these enhancers to regulate tissue-specific genes.
authors: Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston MA 02115, USA.
authors: Milena M
authors: MM
authors: Andzelm
authors: Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston MA 02115, USA.
authors: Timothy J
authors: TJ
authors: Cherry
authors: Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston MA 02115, USA.
authors: David A
authors: DA
authors: Harmin
authors: Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston MA 02115, USA.
authors: Annabel C
authors: AC
authors: Boeke
authors: Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston MA 02115, USA.
authors: Charlotte
authors: C
authors: Lee
authors: Department of Ophthalmology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors: Martin
authors: M
authors: Hemberg
authors: Berman-Gund Laboratory For the Study of Retinal Degenerations, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
authors: Basil
authors: B
authors: Pawlyk
authors: Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston MA 02115, USA.
authors: Athar N
authors: AN
authors: Malik
authors: Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston MA 02115, USA.
authors: Steven W
authors: SW
authors: Flavell
authors: Berman-Gund Laboratory For the Study of Retinal Degenerations, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
authors: Michael A
authors: MA
authors: Sandberg
authors: Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston MA 02115, USA.
authors: Elio
authors: E
authors: Raviola
authors: Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston MA 02115, USA. Electronic address: michael_greenberg@hms.harvard.edu.
authors: Michael E
authors: ME
authors: Greenberg
mesh_terms: D000221:Adaptation, Ocular / Q000235:genetics; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D047369:Chromatin Immunoprecipitation; D004596:Electroretinography; D004622:Embryo, Mammalian; D005136:Eye Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D016678:Genome; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010786:Photoreceptor Cells / Q000502:physiology*; D012160:Retina / Q000166:cytology* / Q000254:growth & development; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D064326:MEF2 Transcription Factors; C578044:Mef2d protein, mouse; D015534:Trans-Activators; C109288:cone rod homeobox protein; D049452:Green Fluorescent Proteins