TBL1XR1 ensures balanced neural developmental through NCOR complex-mediated regulation of the MAPK pathway
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ABSTRACT:
PROVIDER: PRJNA682957 | ENA |
REPOSITORIES: ENA
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Project description:TBL1XR1 gene is associated with multiple developmental disorders presenting several neurological aspects. The relative protein is involved in regulation of important cellular pathways and master regulators of transcriptional output including nuclear receptor repressors, Wnt signaling, and MECP2 protein. However, TBL1XR1 mutations (including complete loss of its functions) have not been experimentally studied in neurological context, leaving a lack of knowledge in the mechanisms at the basis of the diseases. We show that Tbl1xr1 knock-out mice exhibit behavioral and neuronal abnormalities. Either the absence of TBL1XR1, or point mutations interfering with stability/regulation of NCOR complex induced decreased proliferation and increased differentiation in neural progenitors. We suggest that this developmental unbalance is due to the failure in the regulation of MAPK cascade. Together, our results broaden the molecular and functional aftermath of TBL1XR1 deficiency associated with human disorders.
2021-03-16 | GSE162750 | GEO
Project description:TBL1XR1 gene is associated with multiple developmental disorders presenting several neurological aspects. The relative protein is involved in the modulation of important cellular pathways and master regulators of transcriptional output, including nuclear receptor repressors, Wnt signaling, and MECP2 protein. However, TBL1XR1 mutations (including complete loss of its functions) have not been experimentally studied in a neurological context, leaving a knowledge gap in the mechanisms at the basis of the diseases. Here, we show that Tbl1xr1 knock-out mice exhibit behavioral and neuronal abnormalities. Either the absence of TBL1XR1 or its point mutations interfering with stability/regulation of NCOR complex induced decreased proliferation and increased differentiation in neural progenitors. We suggest that this developmental unbalance is due to a failure in the regulation of the MAPK cascade. Taken together, our results broaden the molecular and functional aftermath of TBL1XR1 deficiency associated with human disorders.
| S-EPMC7940385 | biostudies-literature
Project description:Our spatiotemporal data confirmed activation of Tbl1xr1 in hepatocytes after 2/3 hepatectomy. TBL1XR1 is a transcriptional cofactor inducing ubiquitination and degradation of NCoR/SMRT co-repressors and NCoR is a negative regulator of hepatocyte proliferation acting through histone deacetylases (HDACs). We have examined the role of TBL1XR1 in liver regeneration through in vivo shRNA knockdown using adeno-associated viruses (shNC and shTbl1xr1) specifically targeting hepatocytes. The knockdown of Tbl1xr1 results in impair hepatocyte proliferation.To investigate the downstream targets of TBL1XR1 during liver regenration, we here perform the bulk RNA-seq for shNC and shTbl1xr1 at D2 after hepatectomy. Our data show demonstrated that Tbl1xr1 knockdown not only led to reduced cell cycle genes but also to impaired fatty acid β-oxidation as the most obviously affected liver function.
2024-02-05 | GSE254481 | GEO
Project description:Heme is the endogenous ligand for the constitutively repressive REV-ERB nuclear receptors, REV-ERBα (NR1D1) and REV-ERBβ (NR1D2), but how heme regulates REV-ERB activity remains unclear. While cellular studies indicate heme is required for the REV-ERBs to bind the corepressor NCoR and repress transcription, fluorescence-based biochemical assays and crystal structures suggest that heme displaces NCoR. Here, we found that heme artifactually influences detection of NCoR interaction in fluorescence-based assays. Using fluorescence-independent methods, including isothermal titration calorimetry, NMR spectroscopy, and XL-MS, we determined that heme remodels the thermodynamic profile of NCoR binding to REV-ERBβ ligand-binding domain (LBD) and directly increases LBD binding affinity for an NCoR interaction motif. We further report two crystal structures of REV-ERBβ LBD cobound to heme and NCoR peptides, which reveal the heme-dependent NCoR binding mode. By resolving previous contradictory biochemical, structural, and cellular studies, our findings should facilitate renewed progress toward understanding heme-dependent REV-ERB activity.
2021-02-24 | PXD021761 | Pride
Project description:HDAC3 ensures stepwise epidermal stratification via NCoR/SMRT-reliant mechanisms independent of its histone deacetylase activity
| PRJNA564838 | ENA
Project description:Diffuse large B-cell lymphomas (DLBCL) encompass a heterogeneous group of diseases derived from different stages of B-cell differentiation. The most clinically aggressive forms of DLBCL, C5/MCD, carry activating mutations in canonical B-cell signaling pathways, as well as early-occurring hits in the poorly-characterized gene TBL1XR1. Here, we investigated the role of TBL1XR1 mutations in the early steps of malignant transformation. We found that TBL1XR1 mutations disrupt germinal center development, and introduce a cell fate bias towards memory B (MB) cells. At the molecular level, TBL1XR1 mutations trigger a switch, by which the SMRT/HDAC3 co-repressor complex shuttles between the lineage-defining transcription factors BCL6 and BACH2. We further demonstrate that terminal differentiation of TBL1XR1 mutant MB is limited upon recall, and that these MB re-enter the germinal center reaction instead, suggesting a role for these cells as the cell-of-origin of C5/MCD DLBCL.
2020-07-02 | GSE139059 | GEO
Project description:The thyroid hormone receptor (TR) has been proposed to regulate target genes in the absence of triiodothyronine (T3), through the recruitment of the corepressors, NCoR and SMRT. NCoR and SMRT may thus play a key role in both hypothyroidism and resistance to thyroid hormone, though this has never been tested in vivo. To accomplish this we developed mice that express in the liver a NCoR protein (L-NCoR∆ID) that cannot interact with the TR. L-NCoR∆ID mice develop normally, however when made hypothyroid the repression of many positively regulated T3-target genes is abrogated, demonstrating that NCoR plays a specific and sufficient role in repression by the unliganded TR. Remarkably, in the euthyroid state, expression of many T3-targets are also upregulated in L-NCoR∆ID mice, demonstrating that NCoR also determines the magnitude of the response to T3 in euthyroid animals. While positive T3 targets were upregulated in L-NCoR∆ID mice in the hypo and euthyroid state there was less effect seen on negatively regulated T3 target genes. Thus, NCoR is a specific regulator of T3-action in vivo and mediates the activity of the unliganded TR. Furthermore, NCoR may play a key role in determining the differences in individual responses to similar levels of circulating T3. Keywords: NCoR, thyroid hormone signaling, mouse liver, DNA Microarray To better assess the role of NCoR in positive and negative regulation we performed micorarray analysis of gene expression in the livers of euthyroid and hypothyroid control and L-NCoR∆ID mice.
2008-12-03 | E-GEOD-10001 | biostudies-arrayexpress
Project description:The thyroid hormone receptor (TR) has been proposed to regulate target genes in the absence of triiodothyronine (T3), through the recruitment of the corepressors, NCoR and SMRT. NCoR and SMRT may thus play a key role in both hypothyroidism and resistance to thyroid hormone, though this has never been tested in vivo. To accomplish this we developed mice that express in the liver a NCoR protein (L-NCoR∆ID) that cannot interact with the TR. L-NCoR∆ID mice develop normally, however when made hypothyroid the repression of many positively regulated T3-target genes is abrogated, demonstrating that NCoR plays a specific and sufficient role in repression by the unliganded TR. Remarkably, in the euthyroid state, expression of many T3-targets are also upregulated in L-NCoR∆ID mice, demonstrating that NCoR also determines the magnitude of the response to T3 in euthyroid animals. While positive T3 targets were upregulated in L-NCoR∆ID mice in the hypo and euthyroid state there was less effect seen on negatively regulated T3 target genes. Thus, NCoR is a specific regulator of T3-action in vivo and mediates the activity of the unliganded TR. Furthermore, NCoR may play a key role in determining the differences in individual responses to similar levels of circulating T3. Keywords: NCoR, thyroid hormone signaling, mouse liver, DNA Microarray
2008-12-04 | GSE10001 | GEO
Project description:HDAC3 ensures stepwise epidermal stratification via NCoR/SMRT-reliant mechanisms independent of its histone deacetylase activity (HDAC3_KLF4_ChIPseq)
| PRJNA564839 | ENA
Project description:Chromatin modifiers play critical roles in epidermal development, but the functions of histone deacetylases in this context are poorly understood. We find that the Class I HDAC, HDAC3, is expressed broadly in embryonic epidermis, and is required for its orderly stepwise stratification. Stability of HDAC3 protein in vivo is reliant on NCoR and SMRT, which function redundantly in epidermal development. However, point mutations in the NCoR and SMRT Deacetylase Activating Domains, which are required for HDAC3’s enzymatic function, permit normal stratification, indicating that HDAC3’s roles in this context are independent of its histone deacetylase activity. HDAC3 functions both in conjunction with, and independent of, KLF4 to repress premature expression of different sets of terminal differentiation genes and suppresses expression of inflammatory cytokines through a RelA-dependent mechanism. These data identify HDAC3 as a hub coordinating multiple aspects of epidermal barrier acquisition.
2020-08-23 | GSE137232 | GEO