Biology subjects

Akol, I.

Publications and source records attributed to Akol, I..

3 recordsLinked to original sources

bioRxiv2024

The lincRNA Pantr1 is a FOXG1 target gene conferring site-specific chromatin binding of FOXG1

Derailed gene expression programs within the developing nervous system, encompassing both transcriptional and posttranscriptional processes, can cause diverse neurodevelopmental diseases (NDD). The NDD FOXG1-syndrome lacks full understanding of the mechanistic role of its eponymous gene product. While it is known that FOXG1 acts in part at the chromatin by binding to regulative regions, it is unclear what factors control its presence at specific sites. Long non-coding RNAs (lncRNAs) can mediate site-directed transcription factor binding, but their potential role in FOXG1-syndrome has not been described. Here, we show that FOXG1 localisation is regulated at selected loci through the lncRNA Pantr1. We identified FOXG1 as an upstream transcriptional activator of Pantr1 in human and mice. Further, we discovered that FOXG1 has the ability to associate with RNAs. Both, transcriptional regulation of Pantr1 by FOXG1 and association of both partners, build up a regulative network that impacts the localisation of FOXG1 at selected genomic loci. Specifically, Pantr1 facilitates cooperative presence of FOXG1/NEUROD1 at specific sites, and Pantr1 reduction leads to redistribution of FOXG1 to comparably more generic binding sites. The rescue of impaired dendritic outgrowth upon FOXG1 reduction by simultaneous overexpression of Pantr1 underlines the importance of the FOXG1/Pantr1 regulative network. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/610239v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@19ecb05org.highwire.dtl.DTLVardef@22cfbcorg.highwire.dtl.DTLVardef@1748056org.highwire.dtl.DTLVardef@1959e3c_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

DOT1L deletion impairs the development of cortical Parvalbumin-expressing interneurons

The cortical plate is composed of excitatory and inhibitory neurons, the latter of which originate in the ganglionic eminences. From their origin in the ventral telencephalon, interneuron precursors migrate during embryonic development over some distance to reach their final destination in the cortical plate. The histone methyltransferase DOT1L is necessary for proper cortical plate development and layer distribution of glutamatergic neurons, however, its specific role on cortical interneuron development has not yet been explored. Here, we demonstrate that DOT1L affects interneuron development in a cell-autonomous manner. Deletion of Dot1l in MGE-derived interneuron precursor cells results in an overall reduction and altered distribution of GABAergic interneurons in the cortical plate at postnatal day (P) 0. Furthermore, we observed an altered proportion of GABAergic interneurons in the cortex and striatum at P21 with a significant decrease in Parvalbumin (PVALB)-expressing interneurons. Altogether, our results indicate that reduced numbers of cortical interneurons upon DOT1L deletion results from altered post-mitotic differentiation/maturation.

neuroscience↗

bioRxiv2021

Integrative multi-omics analyses reveal multi-modal FOXG1 functions acting on epigenetic processes and in concert with NEUROD1 to regulate synaptogenesis in the mouse hippocampus

BackgroundFOXG1 has important functions for neuronal differentiation and balances excitatory/inhibitory network activity. Mutations in the human FOXG1 gene cause a rare neurodevelopmental disorder, FOXG1-syndrome, which manifests differing phenotypes, including severe cognitive dysfunction, microencephaly, social withdrawal, and communication and memory deficits. Changes at the molecular level underlying these functional abnormalities upon FOXG1 haploinsufficiency are largely unexplored, in human patients as well as in animals modelling the debilitating disease. MethodsWe present multi-omics data and explore comprehensively how FOXG1 impacts neuronal maturation at the chromatin level in the adult mouse hippocampus. We used RNA-, ATAC- and ChIP-sequencing of primary hippocampal neurons and co-immunoprecipitation to explore various levels of epigenetic changes and transcription factor networks acting to alter neuronal differentiation upon reduction of FOXG1. ResultsWe provide the first comprehensive multi-omics data set exploring FOXG1 presence at the chromatin and identifying the consequences of reduced FOXG1 expression in primary hippocampal neurons. Analyzing the multi-omics data, our study reveals that FOXG1 uses various different ways to regulate transcription at the chromatin level. On a genome-wide level, FOXG1 (i) both represses and activates transcription, (ii) binds mainly to enhancer regions, and (iii) bidirectionally alters the epigenetic landscape in regard to levels of H3K27ac, H3K4me3, and chromatin accessibility. Genes affected by the chromatin alterations upon FOXG1 reduction impact synaptogenesis and axonogenesis. This finding emphasizes the importance of FOXG1 to integrate and coordinate transcription of genes necessary for proper neuronal function by acting on a genome-wide level. Interestingly, FOXG1 acts through histone deacetylases (HDACs) and inhibition of HDACs partly rescued transcriptional alterations observed upon FOXG1 reduction. On a more detailed level of analysis, we show that FOXG1 (iv) operates synergistically with NEUROD1. Interestingly, we could not detect a clear hierarchy of these two key transcription factors, but instead provide first evidence that they act in highly concerted and orchestrated manner to control neuronal differentiation. ConclusionsThis integrative and multi-omics view of changes upon FOXG1 reduction reveals an unprecedented multimodality of FOXG1 functions converging on neuronal maturation, fueling novel therapeutic options based on epigenetic drugs to alleviate, at least in part, neuronal dysfunctions.

neuroscience↗