LHX2 Interacts with the NuRD Complex and Regulates Cortical Neuron Subtype Determinants Fezf2 and Sox11
| Autor: | Hari Padmanabhan, Shubha Tole, Saurabh J. Pradhan, Krishanpal Karmodiya, Ullas Kolthur-Seetharam, Upasana Maheshwari, Basabdatta Roy, Zeba Khatri, Sanjeev Galande, Ashwin S. Shetty, Chinthapalli Balaji, Jeffrey D. Macklis, Ritika Gupta, Bhavana Muralidharan |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Development/Plasticity/Repair LIM-Homeodomain Proteins Nerve Tissue Proteins Biology Chromatin remodeling Histone Deacetylases Epigenesis Genetic SOXC Transcription Factors 03 medical and health sciences Mice Pregnancy lamination Nucleosome Animals RBBP4 Research Articles Genetics Cerebral Cortex Neurons cell fate epigenetics Histone deacetylase 2 General Neuroscience Neurogenesis progenitor Mi-2/NuRD complex Chromatin Cell biology Nucleosomes DNA-Binding Proteins 030104 developmental biology specification embryonic structures Female Histone deacetylase Mi-2 Nucleosome Remodeling and Deacetylase Complex Transcription Factors |
| Zdroj: | The Journal of Neuroscience |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | In the developing cerebral cortex, sequential transcriptional programs take neuroepithelial cells from proliferating progenitors to differentiated neurons with unique molecular identities. The regulatory changes that occur in the chromatin of the progenitors are not well understood. During deep layer neurogenesis, we show that transcription factor LHX2 binds to distal regulatory elements ofFezf2andSox11, critical determinants of neuron subtype identity in the mouse neocortex. We demonstrate that LHX2 binds to the nucleosome remodeling and histone deacetylase histone remodeling complex subunits LSD1, HDAC2, and RBBP4, which are proximal regulators of the epigenetic state of chromatin. When LHX2 is absent, active histone marks at theFezf2andSox11loci are increased. Loss of LHX2 produces an increase, and overexpression of LHX2 causes a decrease, in layer 5Fezf2and CTIP2-expressing neurons. Our results provide mechanistic insight into how LHX2 acts as a necessary and sufficient regulator of genes that control cortical neuronal subtype identity.SIGNIFICANCE STATEMENTThe functional complexity of the cerebral cortex arises from an array of distinct neuronal subtypes with unique connectivity patterns that are produced from common progenitors. This study reveals that transcription factor LHX2 regulates the numbers of specific cortical output neuron subtypes by controlling the genes that are required to produce them. Loss or increase in LHX2 during neurogenesis is sufficient to increase or decrease, respectively, a particular subcerebrally projecting population. Mechanistically, LHX2 interacts with chromatin modifying protein complexes to edit the chromatin landscape of its targetsFezf2andSox11, which regulates their expression and consequently the identities of the neurons produced. Thus, LHX2 is a key component of the control network for producing neurons that will participate in cortical circuitry. |
| Databáze: | OpenAIRE |
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