Epigenetic Crosstalk Regulates Neuronal Development

University Of Wisconsin-Madison, Madison WI

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Abstract

Abstract Although most neurons in the mammalian brain are born before birth, neuronal development continues postnatally both in the form of neuronal maturation and in the mode of postnatal neurogenesis. Dysregulation of postnatal neuronal development is linked to a number of neurodevelopmental and neuropsychiatric disorders. Therefore understanding the regulatory mechanism of postnatal neuronal development has significant impact on human health. Epigenetic mechanisms, including DNA methylation and histone modification, play significant roles in brain development and plasticity, as well as in mediating environmental impact on brain functions. The precise mechanism remains unclear. Methyl-CpG binding proteins, including MBD1 and MeCP2 can translate DNA methylation into gene expression changes. MBD1 gene mutations and polymorphism are found in a subset of autistic patients and chromosome 18q21 deletion syndrome. We have shown that MBD1 deficiency in mice results in impaired postnatal neurogenesis, neuronal maturation and behavioral deficits including learning defects, impaired social interaction, anxiety, reduced prepulse inhibition Using genome-wide approaches, we found that although MBD1 is recognized as a transcriptional repressor, majority of MBD1 bound genes showed decreased expression in KO neurons. We also discovered that MBD1 interacts with several proteins in the BAF ( Brg/Brahma-associated factors or SWI/SNF) ATP-dependent chromatin remodeling complex. BAF is critical for neuronal development and mutations of its core components are strongly associated with intellectual disabilities, including schizophrenia and autism. How BAF targets to specific genes remain unclear. An interaction between a known transcriptional activation complex and a canonical transcriptional repressor has not been established. Thus the functional significance of such regulation in neurodevelopment is unclear. Our preliminary data shows that the MBD1 and BAF170 depend on the presence of each other to effectively bind and activate gene expression in developing neurons. Based on these observations, we hypothesize that MBD1 interacts with BAF complex to activate a subset of genes important for neuronal maturation. We will determine whether and how MBD1 interacts with BAF proteins and potential roles of this interaction (Aim 1); whether BAF is important for MBD1 regulation of neurodevelopmental genes (Aim 2) and whether MBD1 and BAF deletion during postnatal development lead to similar social and cognitive behavioral deficits. Our results will unveil novel epigenetic mechanisms regulating neuronal development. (Synomymous: BRM/Smarca2/SNF2L2; BAF47/Smarcb1/SNF5; BAF53b/ACTL6B; BAF170/Smarcc2)