Coordination of Rel Expression by MAP3K4, CBP, and HDAC6 Controls TS cell Phenotype (RNA-seq)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA624653 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11538517.fastq.gz | Fastqsanger.gz | |||
| SRR11538518.fastq.gz | Fastqsanger.gz | |||
| SRR11538519.fastq.gz | Fastqsanger.gz | |||
| SRR11538520.fastq.gz | Fastqsanger.gz |
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Project description:Trophoblast stem cells lack MAP3K4 activity (TSKI4 cells) switch from epithelial phenotype to intermediate phenotype. Loss of epithelial phenotype is due to the loss of CBP histone acetyltransferase activity and the gain of histone deacetylase HDAC6 expression and activity. In our work, we identify a small network of 183 genes whose expression is co-regulated by MAP3K4, CBP, and HDAC6. Further, we define the key role of one of these co-regulated genes, Rel, in inducing epithelial phenotype in intermediate TSKI4 cells.
2020-08-28 | GSE148496 | GEO
Project description:Trophoblast stem cells lack MAP3K4 activity (TSKI4 cells) switch from epithelial phenotype to intermediate phenotype. Loss of epithelial phenotype is due to the loss of CBP histone acetyltransferase activity and the gain of histone deacetylase HDAC6 expression and activity. In our work, we identify a small network of 183 genes whose expression is co-regulated by MAP3K4, CBP, and HDAC6. Further, we define the key role of one of these co-regulated genes, Rel, in inducing epithelial phenotype in intermediate TSKI4 cells. We used microarrays to compare gene expression betweeen mesenchymal TS cells with inactive MAP3K4 (TSKI4 cells) and epithelial TSKI4 cells re-expressing REL (TSKI4R cells)
2020-08-28 | GSE148250 | GEO
Project description:MAP3K4 is a serine/threonine kinase that regulates epithelial to mesenchymal transition (EMT). Trophoblast stem (TS) cells lacking MAP3K4 kinase activity (TSKI4 cells) are in an intermediate state of EMT, having reduced epithelial and increased mesenchymal marker expression. Reduced epithelial gene expression in TSKI4 cells was due to loss of H2BK5 promoter acetylation catalyzed by the histone acetyltransferase CBP. Herein, we show that MAP3K4 also regulates the ubiquitination and degradation of the deacetylase HDAC6. Due to the loss of MAP3K4 kinase activity, TSKI4 cells have elevated HDAC6 expression and activity. Knockdown of HDAC6 in TSKI4 cells restores epithelial features, defining HDAC6 as a key regulator of EMT controlled by MAP3K4. HDAC6 promotes EMT by directly deacetylating H2BK5 on promoters of tight junction genes claudin6 and occludin, inhibiting their expression. Thus, MAP3K4 is a master regulator that coordinates chromatin modifiers, CBP and HDAC6, to regulate the transition between epithelial and mesenchymal states.
2017-03-07 | GSE92394 | GEO
Project description:MAP3K4 is a serine/threonine kinase that regulates epithelial to mesenchymal transition (EMT). Trophoblast stem (TS) cells lacking MAP3K4 kinase activity (TSKI4 cells) are in an intermediate state of EMT, having reduced epithelial and increased mesenchymal marker expression. Reduced epithelial gene expression in TSKI4 cells was due to loss of H2BK5 promoter acetylation catalyzed by the histone acetyltransferase CBP. Herein, we show that MAP3K4 also regulates the ubiquitination and degradation of the deacetylase HDAC6. Due to the loss of MAP3K4 kinase activity, TSKI4 cells have elevated HDAC6 expression and activity. Knockdown of HDAC6 in TSKI4 cells restores epithelial features, defining HDAC6 as a key regulator of EMT controlled by MAP3K4. HDAC6 promotes EMT by directly deacetylating H2BK5 on promoters of tight junction genes claudin6 and occludin, inhibiting their expression. Thus, MAP3K4 is a master regulator that coordinates chromatin modifiers, CBP and HDAC6, to regulate the transition between epithelial and mesenchymal states.
2017-03-07 | GSE92425 | GEO
Project description:Epithelial stem cells self-renew while maintaining multipotency, but the dependence of stem cell properties on maintenance of the epithelial phenotype is unclear. We previously showed that trophoblast stem (TS) cells lacking the protein kinase MAP3K4 maintain properties of both stemness and epithelial-mesenchymal transition (EMT). Here, we show that MAP3K4 controls the activity of the histone acetyltransferase CBP, and that acetylation of histone H2B by CBP is specifically required to maintain the epithelial phenotype. Combined loss of MAP3K4/CBP activity represses expression of epithelial genes and causes TS cells to undergo EMT while maintaining their self-renewal and multipotency properties. The expression profile of MAP3K4 deficient TS cells defines an H2B acetylation regulated gene signature that closely overlaps with that of human breast cancer cells. Taken together, our data define an epigenetic switch that maintains the epithelial phenotype in TS cells and reveal previously unrecognized genes potentially contributing to breast cancer. Three separate trophoblast stem (TS) cell conditions were compared to define the gene expression changes that occur with the induction of epithelial-mesenchymal transition (EMT) in TS cells. These conditions were TS cells differentiated for 4 days (T^Diff), TS cells differentiated for 4-days and isolated following invasion through Matrigel (T^Inv), and TS cells with an inactive MAP3K4 (TS^KI4). All conditions were normalized to wild-type control TS cells (TS^WT). T^Diff and T^Inv were analyzed in triplicate. TS^KI4 was analyzed in duplicate in two independent biological replicates.
2011-05-27 | E-GEOD-27883 | biostudies-arrayexpress
Project description:Epithelial stem cells self-renew while maintaining multipotency, but the dependence of stem cell properties on maintenance of the epithelial phenotype is unclear. We previously showed that trophoblast stem (TS) cells lacking the protein kinase MAP3K4 maintain properties of both stemness and epithelial-mesenchymal transition (EMT). Here, we show that MAP3K4 controls the activity of the histone acetyltransferase CBP, and that acetylation of histone H2B by CBP is specifically required to maintain the epithelial phenotype. Combined loss of MAP3K4/CBP activity represses expression of epithelial genes and causes TS cells to undergo EMT while maintaining their self-renewal and multipotency properties. The expression profile of MAP3K4 deficient TS cells defines an H2B acetylation regulated gene signature that closely overlaps with that of human breast cancer cells. Taken together, our data define an epigenetic switch that maintains the epithelial phenotype in TS cells and reveal previously unrecognized genes potentially contributing to breast cancer.
2011-05-27 | GSE27883 | GEO
Project description:Expression data of TS cells with inactive MAP3K4 (TSKI4 cells) and TSKI4 cells re-expressing REL (TSKI4R cells)
| PRJNA623598 | ENA
Project description:Coordinated gene expression is required for phenotypic switching between epithelial and mesenchymal phenotypes during normal development and in disease states. Trophoblast stem (TS) cells undergo epithelial-mesenchymal transition (EMT) during implantation and placentation. Mechanisms coordinating gene expression during these processes are poorly understood. We have previously demonstrated that MAP3K4-regulated chromatin modifiers CBP and HDAC6 each regulate thousands of genes during EMT in TS cells. Here we show that CBP and HDAC6 coordinate expression of only 183 genes predicted to be critical regulators of phenotypic switching. The highest-ranking co-regulated gene is the NF-κB family member Rel. Although NF-κB is primarily regulated post-transcriptionally, CBP and HDAC6 control Rel transcript levels by binding Rel regulatory regions and controlling histone acetylation. REL re-expression in mesenchymal-like TS cells induces a mesenchymal-epithelial transition. Importantly, REL forms a feedback loop, blocking HDAC6 expression and nuclear localization. Together, our work defines a developmental program coordinating phenotypic switching.
| S-EPMC7455715 | biostudies-literature
Project description:The Tip60 (also known as Kat5) lysine acetyltransferase functions broadly as a transcriptional co-activator that acetylates histones. In contrast, Tip60 functions in embryonic stem cells (ESCs) both to silence genes that promote differentiation and to activate genes required for proliferation. The mechanism by which Tip60 functions as a repressor is unknown. Here we show that the class II histone deacetylase Hdac6 co-purifies with Tip60-p400 complex from ESCs and is necessary for complete silencing of most differentiation genes targeted by Tip60. In contrast to differentiated cells, where Hdac6 is mainly cytoplasmic and does not interact with Tip60, Hdac6 is largely nuclear in ESCs and neural stem cells (NSCs) and interacts with Tip60-p400 in both cell types. Hdac6 is enriched at promoters bound by Tip60-p400 in ESCs, but while Tip60 binds on both sides of transcription start sites (TSSs), Hdac6 binding overlaps with only the downstream Tip60 peak. Surprisingly, Hdac6 does not deacetylate histones at these sites, but rather is required for Tip60 binding. These data suggest that nuclear exclusion of Hdac6 during differentiation plays a major role in modulation of Tip60-p400 function. We determined the genome-wide localization of Tip60 and Hdac6 in mouse ES cells, and examined genomic binding profiles of Tip60 and Hdac6 upon indicated knockdown by ChIP-seq. We examined genomic binding profiles of p400 upon indicated knockdown by ChIP-seq.
2013-11-20 | E-GEOD-42209 | biostudies-arrayexpress