RNA-Seq analysis of wild-type and Hdac3-null E16.5 neurospheres and P0 cerebral cortex
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ABSTRACT:
PROVIDER: PRJNA550355 | ENA |
REPOSITORIES: ENA
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Project description:Histone deacetylase 3 (HDAC3) is a unique epigenetic regulator forming stoichiometric complexes with several other proteins. Patients with mutations in genes encoding these proteins display intellectual disability, implying an important role of HDAC3 in this prevalent disease. Here we report that cerebrum-specific inactivation of the mouse gene causes striking developmental defects in the neocortex, hippocampus and corpus callosum; post-weaning lethality; and abnormal behaviors, including hyperactivity and anxiety. The developmental defects are due to rapid loss of neural stem and progenitor cells (NSPCs), starting at E14.5. Premature neurogenesis and abnormal neuronal migration in the mutant brain alter NSPC homeostasis. Mutant cerebral cortices display augmented DNA damage, apoptosis, and histone hyperacetylation. In agreement with these results, mutant NSPCs are impaired in forming neurospheres in vitro, and treatment of wild-type NSPCs with the HDAC3-specific inhibitor RGFP966 abolishes neurosphere formation. Transcriptomic analyses of neonatal cerebral cortices and cultured neurospheres support that HDAC3 regulates various transcriptional programs through interaction with multiple transcription factors, including NFIB. These findings establish HDAC3 as a major deacetylase critical for perinatal development of the mouse cerebrum and NSPCs, thereby suggesting a direct link of this enzymatic epigenetic regulator to human cerebral and intellectual development. To study the impact of cerebrum specific (Emx1-Cre) deletion of Hdac3 on embryonic neurospheres (cultured in vitro from E16.5 cerebrum) and neocortex from newborn pups (P0).
2019-06-25 | GSE133195 | GEO
Project description:We performed single-cell RNA seq on C57/BL6 mouse back skin at E13.5, E16.5, and P0 to study embryonic hair follicle development. We analyzed 15,086 single cell transcriptome profiles from E13.5, E16.5 and newborn mice (postnatal day 0, P0) dorsal skin cells across hair follicle induction, organogenesis, cytodifferentiation stage. Based on t-distributed Stochastic Neighbor Embedding (tSNE) clustering, we identified 14 cell clusters from skin cells and delineated their cell identity gene expression profile. By using Monocle pseudotime ordering analysis, we constructed epithelium/dermal cell lineage differentiation trajectory and revealed sequential activation of key regulons involved during embryonic hair follicle morphogenesis. Our findings here provide molecular landscape during hair follicle epithelium/dermal cell lineage fate decisions.
2020-07-01 | GSE131498 | GEO
Project description:Primarily cultured neurospheres
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Project description:To identify expression of hematopoetic stem cell antigens in cerebral cortical derived neurospheres Keywords: Compared CD133 positive neurospheres to control GFP-positive neurospheres
2006-10-01 | GSE5171 | GEO
Project description:Seven day old platelet-derived growth factor-generated neurospheres cultured from the embryonic ganglia Keywords: other
2008-03-01 | GSE10614 | GEO
Project description:Single-cell RNA-seq of the developing C57/BL6 mouse back skin at E13.5, E16.5 and P0
| PRJNA543850 | ENA
Project description:Ankrd11 is a potential chromatin regulator implicated in neural development and autism spectrum disorder (ASD) with no known function in the brain. Here, we show that knockdown of Ankrd11 in developing murine or human cortical neural precursors caused decreased proliferation, reduced neurogenesis, and aberrant neuronal positioning. Similar cellular phenotypes and aberrant ASD-like behaviors were observed in Yoda mice carrying a point mutation in the Ankrd11 HDAC-binding domain. Consistent with a role for Ankrd11 in histone acetylation, Ankrd11 was associated with chromatin, colocalized with HDAC3, and expression and histone acetylation of Ankrd11 target genes were altered in Yoda neural precursors. Moreover, the Ankrd11 knockdown-mediated decrease in precursor proliferation was rescued by inhibiting histone acetyltransferase activity or expressing HDAC3. Thus, Ankrd11 is a crucial epigenetic regulator of neural development that controls histone acetylation and gene expression, thereby providing a likely explanation for its association with cognitive dysfunction and ASD. We used microarrays to compare the gene expression profile in embryonic neurospheres prepared from neocortices of WT and Ankrd11Yod/+ mice E14.5 cortical secondary neurosheres 5 days post-passage were collected and total RNA extracted. cDNA was hybridized on Affymetrix Mouse Gene 2.0 ST Array and gene expression was analyzed using Parterk software. In total, 6 Ankrd11Yod/+ and 5 WT embryos were used.
2014-11-15 | E-GEOD-63303 | biostudies-arrayexpress
Project description:Ankrd11 is a potential chromatin regulator implicated in neural development and autism spectrum disorder (ASD) with no known function in the brain. Here, we show that knockdown of Ankrd11 in developing murine or human cortical neural precursors caused decreased proliferation, reduced neurogenesis, and aberrant neuronal positioning. Similar cellular phenotypes and aberrant ASD-like behaviors were observed in Yoda mice carrying a point mutation in the Ankrd11 HDAC-binding domain. Consistent with a role for Ankrd11 in histone acetylation, Ankrd11 was associated with chromatin, colocalized with HDAC3, and expression and histone acetylation of Ankrd11 target genes were altered in Yoda neural precursors. Moreover, the Ankrd11 knockdown-mediated decrease in precursor proliferation was rescued by inhibiting histone acetyltransferase activity or expressing HDAC3. Thus, Ankrd11 is a crucial epigenetic regulator of neural development that controls histone acetylation and gene expression, thereby providing a likely explanation for its association with cognitive dysfunction and ASD. We used microarrays to compare the gene expression profile in embryonic neurospheres prepared from neocortices of WT and Ankrd11Yod/+ mice
2014-11-15 | GSE63303 | GEO
Project description:HDAC3 and HDAC8 are members of class I deacetylases involved in several biological mechanisms and represent a highly sought-after therapeutic target for drug development. It is historically challenging to develop selective deacetylase inhibitors due to their conserved catalytic domains. HDAC3 also has deacetylase-independent activity, which cannot be blocked by conventional enzymatic inhibitors. Recent advances in proteolysis-targeting chimeras (PROTACs) provides an opportunity to eliminate the whole protein selectively, abolishing both enzymatic and scaffolding functions. Here, we report a novel HDAC3/8 dual degrader YX968 that induces highly potent, rapid and selective degradation of both HDAC3 and HDAC8 without trigging pan-HDAC inhibitory effects. Unbiased quantitative proteomics experiments further confirmed its high selectivity. This dual-specific degrader specifically ablates cellular pathways attributed to HDAC3 and HDAC8 and exhibits high potency in killing cancer cells. YX968 represents a new probe for dissecting the complex biological functions of HDAC3 and HDAC8.
2023-07-18 | PXD040941 | Pride
Project description:We have shown that intravenous injection of HDAC3 floxed mice with adeno-associated virus (AAV) expressing Cre depletes hepatic HDAC3, upregulates lipogenic gene expression, and causes fatty liver. When AAV-Flag-HDAC3 wild-type (WT) is co-injected along with AAV-Cre, the exogenous HDAC3 is expressed at endogenous levels and can completely rescue fatty liver phenotype. Here we profile transcriptome of the rescued WT livers in comparison with HDAC3-depleted (KO) livers. 4-months old C57BL/6 male mice were co-injected with AAV-Cre or AAV-Cre plus AAV-Flag-HDAC3. Mice were fed ad libitum and harvested at 5 pm (ZT10) at 2-weeks post-injection. Liver total RNA was extracted and hybridized to Affymetrix Mouse Gene 1.0ST array.
2013-11-25 | E-GEOD-49386 | biostudies-arrayexpress