Similar Datasets
Project description:Spatiotemporal gene expression is the fundamental feature for cellular differentiation, including neurogenesis. The epigenetic mechanism underlying spatiotemporal gene regulation during in vivo cellular differentiation remains largely unknown. The cerebellum contains ~80% of the total number of neurons in the human brain. Granule cells (GCs) constitute the vast majority of cerebellar neurons, and GC genesis is spatiotemporally regulated. Here, we show that Atoh1-Cre-mediated knockout (ACKO) of the Kmt2d gene encoding the lysine methyltransferase KMT2D (MLL4 and a COMPASS-like enzyme) in the cerebellar GC lineage in mice inhibits cerebellar GC differentiation while increasing cerebellar cell proliferation. Kmt2d ACKO impaired cerebellum-associated behaviors and caused facial peculiarity, microcephaly, and smaller body size (Kabuki syndrome-like characteristics) in mice. KMT2D temporally activates neuronal differentiation programs in cerebellar GC lineage. KMT2D-mediated activation of the key neuronal transcription factor genes En2, Pax6, and Myt1l is critical for GC differentiation. KMT2D positively programs super-enhancers/enhancers associated with these genes. Single cell RNA-seq analysis showed that Kmt2d ACKO inhibited the transition of GC progenitor to GCs while having a cell-non-autonomous impact on other cerebellar cells. These findings provide a unique epigenetic mechanism in which KMT2D temporally orchestrates gene expression required for cerebellar GC differentiation by programming neuronal enhancers.
2025-11-14 | GSE282803 | GEO
Project description:Spatiotemporal gene expression is the fundamental feature for cellular differentiation, including neurogenesis. The epigenetic mechanism underlying spatiotemporal gene regulation during in vivo cellular differentiation remains largely unknown. The cerebellum contains ~80% of the total number of neurons in the human brain. Granule cells (GCs) constitute the vast majority of cerebellar neurons, and GC genesis is spatiotemporally regulated. Here, we show that Atoh1-Cre-mediated knockout (ACKO) of the Kmt2d gene encoding the lysine methyltransferase KMT2D (MLL4 and a COMPASS-like enzyme) in the cerebellar GC lineage in mice inhibits cerebellar GC differentiation while increasing cerebellar cell proliferation. Kmt2d ACKO impaired cerebellum-associated behaviors and caused facial peculiarity, microcephaly, and smaller body size (Kabuki syndrome-like characteristics) in mice. KMT2D temporally activates neuronal differentiation programs in cerebellar GC lineage. KMT2D-mediated activation of the key neuronal transcription factor genes En2, Pax6, and Myt1l is critical for GC differentiation. KMT2D positively programs super-enhancers/enhancers associated with these genes. Single cell RNA-seq analysis showed that Kmt2d ACKO inhibited the transition of GC progenitor to GCs while having a cell-non-autonomous impact on other cerebellar cells. These findings provide a unique epigenetic mechanism in which KMT2D temporally orchestrates gene expression required for cerebellar GC differentiation by programming neuronal enhancers.
2025-11-14 | GSE282802 | GEO
Project description:KMT2D controls cerebellar granule cell differentiation by temporally activating neuronal transcriptional factor genes
| PRJNA1190436 | ENA
Project description:KMT2D controls cerebellar granule cell differentiation by temporally activating neuronal transcriptional factor genes [RNA-seq]
| PRJNA1190439 | ENA
Project description:KMT2D controls cerebellar granule cell differentiation by temporally activating neuronal transcriptional factor genes [CUT&RUN]
| PRJNA1190443 | ENA
Project description:The cerebellum contains 62%‒73% of the total number of neurons in the mouse brain. Granule cells (GCs) constitute the vast majority of cerebellar neurons. Single cell RNA-seq analyses showed that Atoh1-Cre-mediated knockout (KO) of the Kmt2d gene encoding the lysine methyltransferase KMT2D (MLL4 and a COMPASS-like enzyme) in the cerebellar GC lineage in mice inhibited cerebellar GC differentiation and downregulated neuron differentiation expression programs. In addition, Kmt2d KO inhibited the transition of GC progenitors to GCs while having a cell-non-autonomous impact on other cerebellar cells.
2025-11-14 | GSE281630 | GEO
Project description:KMT2D is essential for cerebellar granule cell differentiation
| PRJNA1184848 | ENA
Project description:Plexin-B2 deletion leads to aberrant lamination of cerebellar granule neurons (CGNs) and Purkinje cells. Although in the cerebellum Plexin-B2 is only expressed by proliferating CGN precursors in the outer external granule layer (oEGL), its function in CGN development is still elusive. Here, we used 3D imaging, in vivo electroporation and live-imaging techniques to study CGN development in novel cerebellum-specific Plxnb2 conditional knockout mice. We show that proliferating CGNs in Plxnb2 mutants not only escape the oEGL and mix with newborn postmitotic CGNs. Furthermore, motility of mitotic precursors and early postmitotic CGNs is altered. Together, this leads to the formation of ectopic patches of CGNs at the cerebellar surface and an intermingling of normally time-stamped parallel fibers in the molecular layer (ML), and aberrant arborization of Purkinje cell dendrites. There results suggest that Plexin-B2 restricts CGN motility and might have a function in cytokinesis.
| S-EPMC8211449 | biostudies-literature
Project description:Medulloblastoma (MB) is the most common malignant brain tumour in children. The Sonic Hedgehog (SHH)-medulloblastoma subtype arises from the cerebellar granule neuron lineage. Terminally differentiated neurons are incapable of undergoing further cell division, so an effective treatment for this tumour could be to force neuronal differentiation. Differentiation therapy provides a potential alternative for patients with medulloblastoma who harbor mutations that impair cell death pathways (TP53), which is associated a with high mortality. To this end, our goal was to explore epigenetic regulation of cerebellar granule neuron differentiation in medulloblastoma cells. Key regulators were discovered using chromatin immunoprecipitation with high-throughput sequencing. DNA-bound protein and chromatin protein modifications were investigated across all genes. We discovered that Ezh2-mediated tri-methylation of the H3 histone (H3K27me3), occurred on more than half of the 787 genes whose transcription normally increases as granule neurons terminally differentiate. Conditional knockout of Ezh2 led to early initiation of differentiation in granule neuron precursors (GNPs), but only after cell cycle exit had occurred. Similarly, in MB cells, neuronal differentiation could be induced by preventing H3K27me3 modifications using an Ezh2 inhibitor (UNC1999), but only when UNC1999 was combined with forced cell cycle exit driven by a CDK4/6 inhibitor (Palbociclib). Ezh2 emerges as a powerful restraint upon post-mitotic differentiation during normal GNP development and combination of Ezh2 inhibition with cell cycle exit leads to MB cell differentiation.
| S-EPMC11601632 | biostudies-literature
Project description:Long distance migration of differentiating granule cells from the cerebellar upper rhombic lip has been reported in many vertebrates. However, the knowledge about the subcellular dynamics and molecular mechanisms regulating directional neuronal migration in vivo is just beginning to emerge. Here we show by time-lapse imaging in live zebrafish (Danio rerio) embryos that cerebellar granule cells migrate in chain-like structures in a homotypic glia-independent manner. Temporal rescue of zebrafish Cadherin-2 mutants reveals a direct role for this adhesion molecule in mediating chain formation and coherent migratory behavior of granule cells. In addition, Cadherin-2 maintains the orientation of cell polarization in direction of migration, whereas in Cadherin-2 mutant granule cells the site of leading edge formation and centrosome positioning is randomized. Thus, the lack of adhesion leads to impaired directional migration with a mispositioning of Cadherin-2 deficient granule cells as a consequence. Furthermore, these cells fail to differentiate properly into mature granule neurons. In vivo imaging of Cadherin-2 localization revealed the dynamics of this adhesion molecule during cell locomotion. Cadherin-2 concentrates transiently at the front of granule cells during the initiation of individual migratory steps by intramembraneous transport. The presence of Cadherin-2 in the leading edge corresponds to the observed centrosome orientation in direction of migration. Our results indicate that Cadherin-2 plays a key role during zebrafish granule cell migration by continuously coordinating cell-cell contacts and cell polarity through the remodeling of adherens junctions. As Cadherin-containing adherens junctions have been shown to be connected via microtubule fibers with the centrosome, our results offer an explanation for the mechanism of leading edge and centrosome positioning during nucleokinetic migration of many vertebrate neuronal populations.
| S-EPMC2766073 | biostudies-literature