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Title: The role of ATP-dependent chromatin remodelling factors in cortical development
Author: Nitarska, J.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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Epigenetic modifications of DNA and histones play a key role in governing the expression of genes essential during neural development. Histone deacetylase (HDAC) enzymes exert their functions by directly promoting changes in neuronal gene expression through the interaction with chromatin remodelling proteins and specific transcription factors. In cortical neurons, S-nitrosylation of HDAC2 results in transcriptional activation of genes that support neuronal survival and dendritogenesis (Nott et al., 2008). Bead array analysis identified brahma (Brm), a subunit of the ATP-dependent chromatin remodelling complex Brm/Brg-associated factor (BAF), as one of the genes regulated by HDAC2 S-nitrosylation. Expression of mutant form of HDAC2 that cannot be S-nitrosylated decreased Brm protein levels, leading to defects of radial neuronal migration and cortical laminar pattern. Thus, HDAC2 S-nitrosylation is necessary for the correct neuron radial migration during cortical development. HDACs are recruited to chromatin and exert their transcriptional regulatory functions via interaction with other nuclear factors, as part of multiprotein complexes. To identify the binding partners of HDAC2 in cortical neurons, whole sample mass spectrometry analysis was performed. Our analysis revealed a direct interaction of HDAC2 with nucleosome remodelling and histone deacetylase (NuRD) repressor complex. The core ATPase subunit of the NuRD complex includes a family of mutually exclusive chromodomain helicase DNA binding (CHD) proteins, named CHD3, CHD4 and CHD5. In embryonic cortex CHD4 is expressed in proliferating neuronal progenitors and maintained in postmitotic neurons, whereas homologous CHD3 and CHD5 are confined to postmitotic neurons. CHD3, CHD4 and CHD5 are associated with the promoters of neuronal genes indicating that they directly regulate transcriptional programs during neural development. Importantly, down-regulation of CHD3 subunit specifically expressed in postmitotic neurons, results in cortical radial migration defects, confirming the role of NuRD in cortical development. These studies highlight the importance of HDAC2 S-nitrosylation and ATP-dependent chromatin remodelling complexes in cortical development and cortical radial migration.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available