Investigating the role of SMCHD1 in regulating clustered protocadherin (Pcdh) and Hox genes
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE126257 | GEO | 2019/07/27
REPOSITORIES: GEO
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Project description:Investigating the role of SMCHD1 in regulating clustered protocadherin (Pcdh) and Hox genes
| PRJNA521408 | ENA
Project description:Repressor element-1 silencing transcription factor (REST) or neuron-restrictive silencer factor (NRSF) is a zinc-finger (ZF) containing transcriptional repressor that recognizes thousands of neuron-restrictive silencer elements (NRSEs) in mammalian genomes. How REST/NRSF regulates gene expression remains incompletely understood. Here, we investigate the binding pattern and regulation mechanism of REST/NRSF in the clustered protocadherin (PCDH) genes. We find that REST/NRSF directionally forms base-specific interactions with NRSEs via tandem ZFs in an anti-parallel manner but with striking conformational changes. In addition, REST/NRSF recruitment to the HS5-1 enhancer leads to the decrease of long-range enhancer-promoter interactions and downregulation of the clustered PCDH alpha genes. Thus, REST/NRSF represses PCDH alpha gene expression through directional binding to a repertoire of NRSEs within the distal enhancer and variable target genes.
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Project description:To investigate the effect of Smchd1 ablation on de novo X chromosome inactivation (XCI), we derived clonal neural progenitor cells (NPCs) from Smchd1+/+ (wild-type, WT) and Smchd1-/- mouse embryonic stem cells (ES cells; ESC). We generated allele-specific RNA-seq datasets from WT and Smchd1-/- NPCs to examine the effect of Smchd1 ablation on gene silencing. In addition, we produced allele-specific ChIP-seq profiles of H3K4me3, H3K27me3, CTCF, and RAD21 and Xist CHART-seq profiles in WT and Smchd1-/- NPCs to investigate the role of SMCHD1 on the distribution of euchromatin, facultative heterochromatin, architectural proteins, and Xist RNA on the inactive X chromosome (Xi). To determine the localization of SMCHD1 on the Xi, we employed allele-specific DamID-seq to map SMCHD1-binding regions in female mouse embryonic fibroblasts. Furthermore, we performed in situ Hi-C on WT NPCs, Smchd1-/- NPCs, and female ES cells undergoing XCI, in order to explore the role of SMCHD1 in regulating the higher-order structure of the Xi.
2018-06-07 | GSE99991 | GEO
Project description:Cellular individuality is often achieved by stochastic expression of single genes within tandemly-arrayed gene families. This principle is epitomized by the stochastic choice of clustered Protocadherin (Pcdh) genes which generates the extraordinary cell-surface diversity required for neural circuit assembly during development. However, the molecular mechanisms by which this diversity arises are not fully understood. Here, we show that stochastic Pcdh gene choice requires “escape” from silent heterochromatin by a distal transcriptional enhancer. These enhancer/promoter encounters, that lead to promoter derepression, are catalyzed by cohesin, whose processivity, density and stalling at boundaries define the probability of choice of Pcdh genes by determining the probability of enhancer/promoter contacts in mouse olfactory sensory and cortical neurons. We propose that coupling between an epigenetic switch and the modularity of cohesin trajectories allows for different Pcdh profiles to arise across neuronal cell-types, underlying the diversities of their morphologies and functions in the nervous system. More broadly these principles add a layer of regulatory finesse for the generation of transcription diversity from genes arranged in clusters.
2024-07-29 | GSE249430 | GEO
Project description:To investigate the effect of Smchd1 ablation on the chromatin states of select autosomal gene clusters, we derived clonal neural progenitor cells (NPCs) from Smchd1+/+ (wild-type, WT) and Smchd1-/- mouse embryonic stem cells (ES cells; ESC). We generated allele-specific EZH2 ChIP-seq datasets from WT and Smchd1-/- NPCs to examine the effect of Smchd1 ablation on the distribution of Polycomb repressive complex 2 (PRC2).
2021-07-23 | GSE117636 | GEO
Project description:Parents transmit genetic and epigenetic information to their offspring. Maternal effect genes regulate the offspring epigenome to ensure normal development. Here we report that the epigenetic regulator SMCHD1 has a maternal effect on Hox gene expression and skeletal patterning. Maternal SMCHD1, present in the oocyte and preimplantation embryo, prevents precocious activation of Hox genes post-implantation. Without maternal SMCHD1, highly penetrant posterior homeotic transformations occur in the embryo. Hox genes are decorated with Polycomb marks H2AK119ub and H3K27me3 from the oocyte throughout early embryonic development; however, loss of maternal SMCHD1 does not deplete these marks. Therefore, we propose maternal SMCHD1 acts downstream of Polycomb marks to establish a chromatin state necessary for persistent epigenetic silencing and appropriate Hox gene expression later in the developing embryo. This is a striking role for maternal SMCHD1 in long-lived epigenetic effects impacting offspring phenotype.
2022-06-27 | GSE183736 | GEO
Project description:Parents transmit genetic and epigenetic information to their offspring. Maternal effect genes regulate the offspring epigenome to ensure normal development. Here we report that the epigenetic regulator SMCHD1 has a maternal effect on Hox gene expression and skeletal patterning. Maternal SMCHD1, present in the oocyte and preimplantation embryo, prevents precocious activation of Hox genes post-implantation. Without maternal SMCHD1, highly penetrant posterior homeotic transformations occur in the embryo. Hox genes are decorated with Polycomb marks H2AK119ub and H3K27me3 from the oocyte throughout early embryonic development; however, loss of maternal SMCHD1 does not deplete these marks. Therefore, we propose maternal SMCHD1 acts downstream of Polycomb marks to establish a chromatin state necessary for persistent epigenetic silencing and appropriate Hox gene expression later in the developing embryo. This is a striking role for maternal SMCHD1 in long-lived epigenetic effects impacting offspring phenotype.
2022-06-27 | GSE203617 | GEO
Project description:Parents transmit genetic and epigenetic information to their offspring. Maternal effect genes regulate the offspring epigenome to ensure normal development. Here we report that the epigenetic regulator SMCHD1 has a maternal effect on Hox gene expression and skeletal patterning. Maternal SMCHD1, present in the oocyte and preimplantation embryo, prevents precocious activation of Hox genes post-implantation. Without maternal SMCHD1, highly penetrant posterior homeotic transformations occur in the embryo. Hox genes are decorated with Polycomb marks H2AK119ub and H3K27me3 from the oocyte throughout early embryonic development; however, loss of maternal SMCHD1 does not deplete these marks. Therefore, we propose maternal SMCHD1 acts downstream of Polycomb marks to establish a chromatin state necessary for persistent epigenetic silencing and appropriate Hox gene expression later in the developing embryo. This is a striking role for maternal SMCHD1 in long-lived epigenetic effects impacting offspring phenotype. Our overall design it to compare between Smchd1 control and Smchd1 heterozygous samples. We have performed RNA-seq in a differentiation timecourse in 3 replicate mESC of each genotype with 4 timepoints, comparing the Smchd1 heterozygous to the control, at the matched timepoint.
2022-06-27 | GSE203524 | GEO
Project description:Parents transmit genetic and epigenetic information to their offspring. Maternal effect genes regulate the offspring epigenome to ensure normal development. Here we report that the epigenetic regulator SMCHD1 has a maternal effect on Hox gene expression and skeletal patterning. Maternal SMCHD1, present in the oocyte and preimplantation embryo, prevents precocious activation of Hox genes post-implantation. Without maternal SMCHD1, highly penetrant posterior homeotic transformations occur in the embryo. Hox genes are decorated with Polycomb marks H2AK119ub and H3K27me3 from the oocyte throughout early embryonic development; however, loss of maternal SMCHD1 does not deplete these marks. Therefore, we propose maternal SMCHD1 acts downstream of Polycomb marks to establish a chromatin state necessary for persistent epigenetic silencing and appropriate Hox gene expression later in the developing embryo. This is a striking role for maternal SMCHD1 in long-lived epigenetic effects impacting offspring phenotype.
2022-06-27 | GSE183739 | GEO
Project description:Parents transmit genetic and epigenetic information to their offspring. Maternal effect genes regulate the offspring epigenome to ensure normal development. Here we report that the epigenetic regulator SMCHD1 has a maternal effect on Hox gene expression and skeletal patterning. Maternal SMCHD1, present in the oocyte and preimplantation embryo, prevents precocious activation of Hox genes post-implantation. Without maternal SMCHD1, highly penetrant posterior homeotic transformations occur in the embryo. Hox genes are decorated with Polycomb marks H2AK119ub and H3K27me3 from the oocyte throughout early embryonic development; however, loss of maternal SMCHD1 does not deplete these marks. Therefore, we propose maternal SMCHD1 acts downstream of Polycomb marks to establish a chromatin state necessary for persistent epigenetic silencing and appropriate Hox gene expression later in the developing embryo. This is a striking role for maternal SMCHD1 in long-lived epigenetic effects impacting offspring phenotype.
2022-06-27 | GSE183737 | GEO