Brg1 Coordinates Multiple Processes During Retinogenesis and is a Tumor Suppressor in Retinoblastoma

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 in retinal development and retinoblastoma by using molecular and cellular approaches. Brg1 regulated 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, thereby making them more susceptible to retinoblastoma. ChIP-seq analysis provided insight into the underlying molecular mechanisms of these complex Brg1-regulated cellular processes during retinal development.

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Aldiri I, Ajioka I, Xu B, Zhang J, Chen X, Benavente C, Finkelstein D, Johnson D, Akiyama J, Pennacchio LA, Dyer MA