title: Brg1 coordinates multiple processes during retinogenesis and is a tumor suppressor in retinoblastoma.
abstract: Retinal development requires precise temporal and spatial coordination of cell cycle exit, cell fate specification, cell migration and differentiation. When this process is disrupted, retinoblastoma, a developmental tumor of the retina, can form. Epigenetic modulators are central to precisely coordinating developmental events, and many epigenetic processes have been implicated in cancer. Studying epigenetic mechanisms in development is challenging because they often regulate multiple cellular processes; therefore, elucidating the primary molecular mechanisms involved can be difficult. Here we explore the role of Brg1 (Smarca4) in retinal development and retinoblastoma in mice using molecular and cellular approaches. Brg1 was found to regulate retinal size by controlling cell cycle length, cell cycle exit and cell survival during development. Brg1 was not required for cell fate specification but was required for photoreceptor differentiation and cell adhesion/polarity programs that contribute to proper retinal lamination during development. The combination of defective cell differentiation and lamination led to retinal degeneration in Brg1-deficient retinae. Despite the hypocellularity, premature cell cycle exit, increased cell death and extended cell cycle length, retinal progenitor cells persisted in Brg1-deficient retinae, making them more susceptible to retinoblastoma. ChIP-Seq analysis suggests that Brg1 might regulate gene expression through multiple mechanisms.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Issam
authors.initials: I
authors.lastname: Aldiri
authors.affiliation: Center for Brain Integration Research (CBIR), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan.
authors.forename: Itsuki
authors.initials: I
authors.lastname: Ajioka
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Beisi
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jiakun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Benavente
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.affiliation: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Dianna
authors.initials: D
authors.lastname: Johnson
authors.affiliation: Lawrence Berkeley National Laboratory, Genomics Division, Berkeley, CA 94701, USA Department of Energy, Joint Genome Institute, Walnut Creek, CA 94598, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Akiyama
authors.affiliation: Lawrence Berkeley National Laboratory, Genomics Division, Berkeley, CA 94701, USA Department of Energy, Joint Genome Institute, Walnut Creek, CA 94598, USA.
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA michael.dyer@stjude.org.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dyer
mesh_terms: D000818:Animals; D017209:Apoptosis; D019521:Body Patterning; D002448:Cell Adhesion; D002453:Cell Cycle; D002454:Cell Differentiation; D019070:Cell Lineage; D002465:Cell Movement; D049109:Cell Proliferation; D004265:DNA Helicases / Q000235:genetics* / Q000502:physiology*; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D051379:Mice; D008850:Microphthalmos / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology*; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012175:Retinoblastoma / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D019076:Transgenes
chemical_list: D009687:Nuclear Proteins; D014157:Transcription Factors; C513194:Smarca4 protein, mouse; D004265:DNA Helicases
keywords: Epigenetics; Mouse; Retina development; Retinoblastoma; SWI/SNF