LMTK3 Represses Tumour Suppressor-Like Genes through Chromatin Remodeling in Breast Cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE70385 | GEO | 2015/06/30
SECONDARY ACCESSION(S): PRJNA288494
REPOSITORIES: GEO
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Project description:LMTK3 is an oncogenic receptor tyrosine kinase (RTK) implicated in various types of cancer including breast, lung, gastric and colorectal. It is localized in different cellular compartments but its nuclear function has not been investigated thus far. We have mapped LMTK3 binding across the genome using ChIP-seq and found that LMTK3 binding events are correlated with repressive chromatin markers. We further identified KRAB associated protein-1 (KAP1) as a novel binding partner of LMTK3. The LMTK3/KAP1 interaction is stabilized by PP1_, which suppresses KAP1 phosphorylation specifically at LMTK3-associated chromatin regions, inducing chromatin condensation and resulting in transcriptional repression of LMTK3-bound tumour suppressor-like genes. Furthermore, LMTK3 functions at enhancer regions in tethering the chromatin to the nuclear periphery, resulting in H3K9me3 modification and gene silencing. In summary, we propose a new model where a scaffolding function of nuclear LMTK3 promotes cancer progression through chromatin remodeling, revealing a new mechanism of RTK activity. Examination of LMTK3 binding profile in 2 cell types.
2015-06-30 | E-GEOD-70385 | biostudies-arrayexpress
Project description:LMTK3 is an oncogenic receptor tyrosine kinase (RTK) implicated in various types of cancer including breast, lung, gastric and colorectal. It is localized in different cellular compartments but its nuclear function has not been investigated thus far. We have mapped LMTK3 binding across the genome using ChIP-seq and found that LMTK3 binding events are correlated with repressive chromatin markers. We further identified KRAB associated protein-1 (KAP1) as a binding partner of LMTK3. The LMTK3/KAP1 interaction is stabilized by PP1α, which suppresses KAP1 phosphorylation specifically at LMTK3-associated chromatin regions, inducing chromatin condensation and resulting in transcriptional repression of LMTK3-bound tumour suppressor-like genes. Furthermore, LMTK3 functions at enhancer regions in tethering the chromatin to the nuclear periphery, resulting in H3K9me3 modification and gene silencing. In summary, we propose a model where a scaffolding function of nuclear LMTK3 promotes cancer progression through chromatin remodeling, revealing a previously undescribed mechanism of RTK activity.
2019-10-30 | PXD002399 | Pride
Project description:Chromatin remodeling is fundamental for B cell differentiation. Here, we explored the role in this process of KAP1, the cofactor of KRAB-ZFP transcriptional repressors. B lymphoid-specific Kap1 knockout mice displayed reduced numbers of mature B cells, lower steady-state levels of antibodies and accelerated rates of decay of neutralizing antibodies following viral immunization. Transcriptome analyses of Kap1-deleted B splenocytes revealed an upregulation of PTEN, the enzymatic counter-actor of PIK3 signaling, and of genes encoding DNA damage response factors, cell-cycle regulators and chemokine receptors. ChIP/seq studies established that KAP1 bound at or close to a number of these genes, and controlled chromatin status at their promoters. Genome-wide, KAP1-binding sites avoided active B cell-specific enhancers and were enriched in repressive histone marks, further supporting a role for this molecule in gene silencing in vivo. Likely responsible for tethering KAP1 to at least some of these targets, a discrete subset of KRAB-ZFPs is enriched in B lymphocytes. This work thus reveals the role of KRAB/KAP1-mediated epigenetic regulation in B cell development and homeostasis. Examination of KAP1 binding sites and H3K9me3 enriched regions in KAP1 wild type and KO mouse B splenocytes.
2012-05-16 | E-GEOD-36850 | biostudies-arrayexpress
Project description:Chromatin remodelling at specific genomic loci controls lymphoid differentiation. Here, we investigated the role played in this process by Kruppel-Associated Box (KRAB)- Associated Protein 1 (KAP1), the universal cofactor of KRAB-zinc finger proteins (-ZFPs), a tetrapod-restricted family of transcriptional repressors. T cell-specific Kap1-deleted mice displayed a significant expansion of immature thymocytes, imbalances in CD4+/CD8+ cell ratios and impaired responses to TCR stimulation when compared to littermate KAP1 control mice. Transcriptome and chromatin studies revealed that KAP1 binds T cell-specific cis-acting regulatory elements marked by the H3K9me3 repressive mark and enriched in Ikaros/NuRD complexes. Also, KAP1 directly controls the expression of several genes involved in TCR and cytokine signalling. Among these, regulation of FoxO1 seems to play a major role in this system. Likely responsible for tethering KAP1 to at least part of its genomic targets, a small number of KRAB-ZFPs are selectively expressed in T lymphoid cells. These results reveal the so-far unsuspected yet important role of KAP1-mediated epigenetic regulation in T lymphocyte differentiation and activation. Examination of KAP1 binding sites and H3K9me3-enriched regions in wild type and KAP1 KO mouse thymocytes.
2012-12-16 | E-GEOD-38579 | biostudies-arrayexpress
Project description:Chromatin remodeling is fundamental for B cell differentiation. Here, we explored the role in this process of KAP1, the cofactor of KRAB-ZFP transcriptional repressors. B lymphoid-specific Kap1 knockout mice displayed reduced numbers of mature B cells, lower steady-state levels of antibodies and accelerated rates of decay of neutralizing antibodies following viral immunization. Transcriptome analyses of Kap1-deleted B splenocytes revealed an upregulation of PTEN, the enzymatic counter-actor of PIK3 signaling, and of genes encoding DNA damage response factors, cell-cycle regulators and chemokine receptors. ChIP/seq studies established that KAP1 bound at or close to a number of these genes, and controlled chromatin status at their promoters. Genome-wide, KAP1-binding sites avoided active B cell-specific enhancers and were enriched in repressive histone marks, further supporting a role for this molecule in gene silencing in vivo. Likely responsible for tethering KAP1 to at least some of these targets, a discrete subset of KRAB-ZFPs is enriched in B lymphocytes. This work thus reveals the role of KRAB/KAP1-mediated epigenetic regulation in B cell development and homeostasis. Follicular (FO) and Transcriptional 2 Follicular Progenitor (T2-FP) B cells were sorted out from 3 CD19-Cre/Kap1flox (KAP1 KO in the B lineage) mice and 3 wt/Kap1flox littermate controls
2012-05-16 | E-GEOD-34446 | biostudies-arrayexpress
Project description:The modulation of chromatin status at specific genomic loci controls lymphoid differentiation. Here, we investigated the role played in this process by KAP1, the universal cofactor of KRAB-containing Zinc Finger Proteins (KRAB-ZFPs), a tetrapod-restricted family of transcriptional repressors. T cell-specific Kap1 knockout mice displayed a significant expansion of immature thymocytes and imbalances in the ratios of mature T cells in the thymus and the spleen, with impaired responses to TCR stimulation. Transcriptome and chromatin studies revealed that KAP1 directly controls the expression of a number of genes involved in TCR and cytokine signalling, among which Traf1 and FoxO1, and is strongly associated with cis-acting regulatory elements marked by the H3K9me3 repressive mark on the genome of thymic T cells. Likely responsible for tethering KAP1 to at least part of its genomic targets, a small number of KRAB/ZFPs are selectively expressed in T lymphoid cells. These results reveal the so far unsuspected yet important role of KRAB/KAP1-mediated epigenetic regulation in T lymphocyte differentiation and activation. Cells were harvested form the thymus of 3 CD4-Cre/Kap1flox (KAP1 KO in the T lineage) mice and 3 wt/Kap1flox littermate controls
2012-12-16 | E-GEOD-34447 | biostudies-arrayexpress
Project description:Chromatin remodeling is fundamental for B cell differentiation. Here, we explored the role in this process of KAP1, the cofactor of KRAB-ZFP transcriptional repressors. B lymphoid-specific Kap1 knockout mice displayed reduced numbers of mature B cells, lower steady-state levels of antibodies and accelerated rates of decay of neutralizing antibodies following viral immunization. Transcriptome analyses of Kap1-deleted B splenocytes revealed an upregulation of PTEN, the enzymatic counter-actor of PIK3 signaling, and of genes encoding DNA damage response factors, cell-cycle regulators and chemokine receptors. ChIP/seq studies established that KAP1 bound at or close to a number of these genes, and controlled chromatin status at their promoters. Genome-wide, KAP1-binding sites avoided active B cell-specific enhancers and were enriched in repressive histone marks, further supporting a role for this molecule in gene silencing in vivo. Likely responsible for tethering KAP1 to at least some of these targets, a discrete subset of KRAB-ZFPs is enriched in B lymphocytes. This work thus reveals the role of KRAB/KAP1-mediated epigenetic regulation in B cell development and homeostasis.
2012-05-17 | GSE34446 | GEO
Project description:Chromatin remodeling is fundamental for B cell differentiation. Here, we explored the role in this process of KAP1, the cofactor of KRAB-ZFP transcriptional repressors. B lymphoid-specific Kap1 knockout mice displayed reduced numbers of mature B cells, lower steady-state levels of antibodies and accelerated rates of decay of neutralizing antibodies following viral immunization. Transcriptome analyses of Kap1-deleted B splenocytes revealed an upregulation of PTEN, the enzymatic counter-actor of PIK3 signaling, and of genes encoding DNA damage response factors, cell-cycle regulators and chemokine receptors. ChIP/seq studies established that KAP1 bound at or close to a number of these genes, and controlled chromatin status at their promoters. Genome-wide, KAP1-binding sites avoided active B cell-specific enhancers and were enriched in repressive histone marks, further supporting a role for this molecule in gene silencing in vivo. Likely responsible for tethering KAP1 to at least some of these targets, a discrete subset of KRAB-ZFPs is enriched in B lymphocytes. This work thus reveals the role of KRAB/KAP1-mediated epigenetic regulation in B cell development and homeostasis.
2012-05-17 | GSE36850 | GEO
Project description:We used ChIP-seq to assess how abolition of KRAB binding by KAP1 (through structure-guided mutations in the KAP1-KRAB binding interface) changed the distribution of KAP1 on chromatin genome-wide.
2022-10-10 | GSE215015 | GEO
Project description:We performed a genome-scale ChIP-chip comparison of two modifications (trimethylation of lysine 9 and trimethylation of lysine 27) of histone H3 in Ntera2 testicular carcinoma cells and in three different anatomical sources of primary human fibroblasts. We found that in each of the cell types the two modifications were differentially enriched at the promoters of the two largest classes of transcription factors. Specifically, zinc finger genes were bound by H3me3K9 and homeobox genes were bound by H3me3K27. We have previously shown that the PRC2 complex is responsible for mediating trimethylation of lysine 27 of histone H3 in human cancer cells. In contrast, there is little overlap between H3me3K9 targets and components of the PRC2 complex, suggesting that a different histone methyltransferase is responsible for the H3me3K9 modification. Previous studies have shown that SETDB1 can trimethylate H3 on lysine 9, using in vitro or artificial tethering assays. SETDB1 is thought to be recruited to chromatin by complexes containing the KAP1 co-repressor. To determine if a KAP1-containing complex mediates trimethylation of the identified H3me3K9 targets, we performed ChIP-chip assays and identified KAP1 target genes using human 5kb promoter arrays. We found that a large number of promoters of zinc finger transcription factors were bound by both KAP1 and H3me3K9 in normal and cancer cells. To expand our studies of KAP1, we next performed a complete genomic analysis of KAP1 binding using a 38 array tiling set, identifying ~7000 KAP1 binding sites. The identified KAP1 targets were highly enriched for C2H2 zinc fingers, especially those containing KRAB domains. Interestingly, although most KAP1 binding sites were within core promoter regions, the binding sites near ZNF genes were greatly enriched within transcribed regions of the target genes. Because KAP1 is recruited to the DNA via interaction with KRAB-ZNF proteins, we suggest that expression of KRAB-ZNF genes may be controlled via an auto-regulatory mechanism involving KAP1. Keywords: Human whole genome tiling array
2007-09-29 | GSE8667 | GEO