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KMT2D controls cerebellar granule cell differentiation by temporally activating neuronal transcriptional factor genes [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE282803 | GEO | 2025/11/14

REPOSITORIES: GEO

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KMT2D controls cerebellar granule cell differentiation by temporally activating neuronal transcriptional factor genes [CUT&RUN]

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

KMT2D is essential for cerebellar granule cell differentiation

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Temporal analysis of enhancers during mouse brain development reveals dynamic regulatory function and identifies novel regulators of cerebellar development.

Project description:In this study, we identified active enhancers in the mouse cerebellum at embryonic and postnatal stages establishing the first catalog of enhancers active during embryonic cerebellum development. The majority of cerebellar enhancers have dynamic activity between embryonic and postnatal development. Cerebellar enhancers were enriched for neural transcription factor binding sites with temporally specific expression. Putative gene targets displayed spatially restricted expression patterns, indicating cell-type specific expression regulation. Functional analysis of target genes indicated that enhancers regulate processes spanning several developmental epochs such as specification, differentiation and maturation. We use these analyses to discover one novel regulator and one novel marker of cerebellar development: Bhlhe22 and Pax3, respectively. We identified an enrichment of de novo mutations and variants associated with autism spectrum disorder in cerebellar enhancers. Our study provides insight into the dynamics of gene expression regulation by enhancers in the developing brain and delivers a rich resource of novel gene-enhancer associations providing a basis for future in-depth studies in the cerebellum.

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KMT2D controls cerebellar granule cell differentiation by temporally activating neuronal transcriptional factor genes

Project description:KMT2D controls cerebellar granule cell differentiation by temporally activating neuronal transcriptional factor genes

| PRJNA1190436 | ENA

KMT2D controls cerebellar granule cell differentiation by temporally activating neuronal transcriptional factor genes [CUT&RUN]

Project description:KMT2D controls cerebellar granule cell differentiation by temporally activating neuronal transcriptional factor genes [CUT&RUN]

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KMT2D controls cerebellar granule cell differentiation by temporally activating neuronal transcriptional factor genes [RNA-seq]

Project description:KMT2D controls cerebellar granule cell differentiation by temporally activating neuronal transcriptional factor genes [RNA-seq]

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Transcriptomic profile of germinal center B cells from conditional GC-specific (Cg1-Cre) Crebbp-HET, Kmt2d-HET, and compound Crebbp-HET/Kmt2d-HET mice, with littermate controls

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Chromatin accessibility profiling of developing cerebellar granule neurons identifies novel neuronal enhancers and reveals a role for Zic transcription factors in neuronal maturation

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32ec0dbb-03e4-429e-b406-c610c3ca60f9 - samples

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