NFIB-Mediated Repression of the Epigenetic Factor Ezh2 Regulates Cortical Development

Epigenetic mechanisms are essential in regulating neural progenitor cell self-renewal, with the chromatin-modifying protein Enhancer of zeste homolog 2 (EZH2) emerging as a central player in promoting progenitor cell self-renewal during cortical development. Despite this, how Ezh2 is itself regulated remains unclear. Here, we demonstrate that the transcription factor nuclear factor IB (NFIB) plays a key role in this process. Nfib−/− mice exhibit an increased number of proliferative ventricular zone cells that express progenitor cell markers and upregulation of EZH2 expression within the neocortex and hippocampus. NFIB binds to the Ezh2 promoter and overexpression of NFIB represses Ezh2 transcription. Finally, key downstream targets of EZH2-mediated epigenetic repression are misregulated in Nfib−/− mice. Collectively, these results suggest that the downregulation of Ezh2 transcription by NFIB is an important component of the process of neural progenitor cell differentiation during cortical development.

[1]  L. Richards,et al.  NFIX regulates neural progenitor cell differentiation during hippocampal morphogenesis. , 2014, Cerebral cortex.

[2]  M. Mann,et al.  The chromodomain helicase Chd4 is required for Polycomb‐mediated inhibition of astroglial differentiation , 2013, The EMBO journal.

[3]  M. Olah,et al.  Dynamic Changes in Ezh2 Gene Occupancy Underlie Its Involvement in Neural Stem Cell Self-Renewal and Differentiation towards Oligodendrocytes , 2012, PloS one.

[4]  L. Richards,et al.  Nuclear factor one X regulates the development of multiple cellular populations in the postnatal cerebellum , 2011, The Journal of comparative neurology.

[5]  A. Ferguson-Smith,et al.  Epigenetic regulation of the neural transcriptome: the meaning of the marks , 2010, Nature Neuroscience.

[6]  A. Tarakhovsky,et al.  Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex , 2010, Proceedings of the National Academy of Sciences.

[7]  L. Richards,et al.  NFIA Controls Telencephalic Progenitor Cell Differentiation through Repression of the Notch Effector Hes1 , 2010, The Journal of Neuroscience.

[8]  R. Gronostajski,et al.  Targets of the nuclear factor I regulon involved in early and late development of postmitotic cerebellar granule neurons , 2010, Journal of neuroscience research.

[9]  L. Richards,et al.  Multiple non-cell-autonomous defects underlie neocortical callosal dysgenesis in Nfib-deficient mice , 2009, Neural Development.

[10]  M. Vidal,et al.  Polycomb Limits the Neurogenic Competence of Neural Precursor Cells to Promote Astrogenic Fate Transition , 2009, Neuron.

[11]  M. Serrano,et al.  Polycomb Mediated Epigenetic Silencing and Replication Timing at the INK4a/ARF Locus during Senescence , 2009, PloS one.

[12]  J. Kohyama,et al.  Committed neuronal precursors confer astrocytic potential on residual neural precursor cells. , 2009, Developmental cell.

[13]  L. Richards,et al.  Specific Glial Populations Regulate Hippocampal Morphogenesis , 2008, The Journal of Neuroscience.

[14]  Ryoichiro Kageyama,et al.  Dynamic Notch signaling in neural progenitor cells and a revised view of lateral inhibition , 2008, Nature Neuroscience.

[15]  L. Richards,et al.  Nuclear factor I gene expression in the developing forebrain , 2008, The Journal of comparative neurology.

[16]  Webster K. Cavenee,et al.  Feedback Circuit among INK4 Tumor Suppressors Constrains Human Glioblastoma Development , 2008, Cancer cell.

[17]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[18]  R. Gronostajski,et al.  Nuclear Factor I Coordinates Multiple Phases of Cerebellar Granule Cell Development via Regulation of Cell Adhesion Molecules , 2007, The Journal of Neuroscience.

[19]  D. Carrasco,et al.  Expression of p16Ink4a compensates for p18Ink4c loss in cyclin-dependent kinase 4/6-dependent tumors and tissues. , 2007, Cancer research.

[20]  David J. Anderson,et al.  The Transcription Factor NFIA Controls the Onset of Gliogenesis in the Developing Spinal Cord , 2006, Neuron.

[21]  J. Zeitlinger,et al.  Polycomb complexes repress developmental regulators in murine embryonic stem cells , 2006, Nature.

[22]  M. Vallejo,et al.  Nuclear factor‐I regulates glial fibrillary acidic protein gene expression in astrocytes differentiated from cortical precursor cells , 2006, Journal of neurochemistry.

[23]  Megan F. Cole,et al.  Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells , 2006, Cell.

[24]  Feng Chen,et al.  Statistical analysis of real-time PCR data , 2006, BMC Bioinformatics.

[25]  L. Richards,et al.  The Transcription Factor Gene Nfib Is Essential for both Lung Maturation and Brain Development , 2005, Molecular and Cellular Biology.

[26]  Hengbin Wang,et al.  Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing , 2002, Science.

[27]  R. Gronostajski,et al.  Disruption of the murine nuclear factor I-A gene (Nfia) results in perinatal lethality, hydrocephalus, and agenesis of the corpus callosum. , 1999, Proceedings of the National Academy of Sciences of the United States of America.