Histone methylation regulator PTIP is required to maintain normal and leukemic bone marrow niches
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ABSTRACT:
PROVIDER: PRJNA485240 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7663300_1.fastq.gz | Fastqsanger.gz | |||
| SRR7663300_2.fastq.gz | Fastqsanger.gz | |||
| SRR7663297_1.fastq.gz | Fastqsanger.gz | |||
| SRR7663297_2.fastq.gz | Fastqsanger.gz | |||
| SRR7663298_1.fastq.gz | Fastqsanger.gz |
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Project description:The bone is essential for locomotion, calcium storage and harboring the hematopoietic stem cells (HSCs) that supply the body with mature blood cells throughout life. HSCs reside at the interface of the bone and bone marrow (BM), where active bone remodeling takes place. Although the cellular components of the BM niche have been characterized, little is known about its epigenetic regulation. Here we find that the histone methylation regulator PTIP (Pax interaction with transcription-activation domain protein-1) is required to maintain the integrity of the BM niche by promoting osteoclast differentiation. PTIP directly promotes chromatin changes required for the expression of Pparg (Peroxisome proliferator-activated receptor-γ), a transcription factor essential for osteoclastogenesis. PTIP deletion leads to a drastic reduction of HSCs in the BM and induces extramedullary hematopoiesis. Furthermore, exposure of acute myeloid leukemia cells to a PTIP-deficient BM microenvironment leads to a reduction in leukemia initiating cells (LICs) and increased survival upon transplantation. Taken together, our data identify PTIP as a novel epigenetic regulator of osteoclastogenesis that is required for the integrity of the BM niche to sustain both normal hematopoiesis and leukemia.
2018-09-24 | GSE118329 | GEO
Project description:The bone is essential for locomotion, calcium storage, and harboring the hematopoietic stem cells (HSCs) that supply the body with mature blood cells throughout life. HSCs reside at the interface of the bone and bone marrow (BM), where active bone remodeling takes place. Although the cellular components of the BM niche have been characterized, little is known about its epigenetic regulation. Here we find that the histone methylation regulator PTIP (Pax interaction with transcription-activation domain protein-1) is required to maintain the integrity of the BM niche by promoting osteoclast differentiation. PTIP directly promotes chromatin changes required for the expression of Pparγ (peroxisome proliferator-activated receptor-γ), a transcription factor essential for osteoclastogenesis. PTIP deletion leads to a drastic reduction of HSCs in the BM and induces extramedullary hematopoiesis. Furthermore, exposure of acute myeloid leukemia cells to a PTIP-deficient BM microenvironment leads to a reduction in leukemia-initiating cells and increased survival upon transplantation. Taken together, our data identify PTIP as an epigenetic regulator of osteoclastogenesis that is required for the integrity of the BM niche to sustain both normal hematopoiesis and leukemia.
| S-EPMC6205459 | biostudies-literature
Project description:PPARg and C/EBPa cooperate to control preadipocyte differentiation (adipogenesis). However, the factors that regulate PPARg and C/EBPa expression during adipogenesis remain largely unclear. Here we show PTIP, a protein that associates with histone H3K4 methyltransferases, regulates PPARg and C/EBPa expression in mouse embryonic fibroblasts (MEFs) and during preadipocyte differentiation. PTIP deletion in MEFs leads to marked decreases of PPARg expression and PPARg-stimulated C/EBPα expression. Further, PTIP is essential for induction of PPARg and C/EBPa expression during preadipocyte differentiation. Deletion of PTIP impairs the enrichment of H3K4 trimethylation and RNA polymerase II on PPARg and C/EBPa promoters. Accordingly, PTIP-/- MEFs and preadipocytes all show striking defects in adipogenesis. Furthermore, rescue of the adipogenesis defect in PTIP-/- MEFs requires co-expression of PPARg and C/EBPa. Finally, deletion of PTIP in brown adipose tissue significantly reduces tissue weight in mice. Thus, by regulating PPARg and C/EBPa expression, PTIP plays a critical role in adipogenesis.
2009-05-29 | GSE16263 | GEO
Project description:PPARg and C/EBPa cooperate to control preadipocyte differentiation (adipogenesis). However, the factors that regulate PPARg and C/EBPa expression during adipogenesis remain largely unclear. Here we show PTIP, a protein that associates with histone H3K4 methyltransferases, regulates PPARg and C/EBPa expression in mouse embryonic fibroblasts (MEFs) and during preadipocyte differentiation. PTIP deletion in MEFs leads to marked decreases of PPARg expression and PPARg-stimulated C/EBPα expression. Further, PTIP is essential for induction of PPARg and C/EBPa expression during preadipocyte differentiation. Deletion of PTIP impairs the enrichment of H3K4 trimethylation and RNA polymerase II on PPARg and C/EBPa promoters. Accordingly, PTIP-/- MEFs and preadipocytes all show striking defects in adipogenesis. Furthermore, rescue of the adipogenesis defect in PTIP-/- MEFs requires co-expression of PPARg and C/EBPa. Finally, deletion of PTIP in brown adipose tissue significantly reduces tissue weight in mice. Thus, by regulating PPARg and C/EBPa expression, PTIP plays a critical role in adipogenesis. To identify PTIP-regulated genes, immortalized PTIP conditional knockout PTIPflox/flox MEFs were infected with retroviruses expressing either Cre recombinase or vector alone. We prepared duplicated RNAs from either vector or Cre infected cells (PTIP+/+ or PTIP-/-) for 4 affymetrix microarrays.
2009-05-29 | E-GEOD-16263 | biostudies-arrayexpress
Project description:Innate immune cells including myeloid cells exhibit dynamic cellular switches during inflammatory and immune responses against infection. These processes are tightly regulated at different levels including the cis-regulatory elements of immune cells. However, it remains unclear how the dynamic states of cis-regulatory elements of innate immune cells are controlled during inflammatory responses. Here we found that histone methylation regulator PTIP orchestrates inflammatory responses of macrophages through regulating acetylation state of enhancers and promoters. Rapid elevated expression of PTIP is observed in primary human and mouse macrophages upon lipopolysaccharide (LPS) stimulation. Loss of PTIP represses transcription of pro-inflammatory genes, and activates expression of anti-inflammatory genes. Mechanistically, we found that, independent of its function in histone methylation, PTIP interacts with acetyltransferase p300 and deacetylase HDACs, and serves as a beacon to recruit them to specific sites of inflammatory genes respectively. PTIP deficiency alters H3K27 acetylation state of cis-regulatory elements of inflammatory genes. Moreover, PTIP and c-JUN shape a positive and feedforward regulatory circuit. In addition, PTIP deletion sustains immunosuppressive function of tumor-associated macrophages (TAMs) and promotes tumor growth. Overall, our findings uncover a critical role of PTIP in altering the acetylation state of cis-regulatory regions and fine-tuning the inflammatory responses of innate immune cells.
2022-12-30 | GSE163463 | GEO
Project description:Innate immune cells including myeloid cells exhibit dynamic cellular switches during inflammatory and immune responses against infection. These processes are tightly regulated at different levels including the cis-regulatory elements of immune cells. However, it remains unclear how the dynamic states of cis-regulatory elements of innate immune cells are controlled during inflammatory responses. Here we found that histone methylation regulator PTIP orchestrates inflammatory responses of macrophages through regulating acetylation state of enhancers and promoters. Rapid elevated expression of PTIP is observed in primary human and mouse macrophages upon lipopolysaccharide (LPS) stimulation. Loss of PTIP represses transcription of pro-inflammatory genes, and activates expression of anti-inflammatory genes. Mechanistically, we found that, independent of its function in histone methylation, PTIP interacts with acetyltransferase p300 and deacetylase HDACs, and serves as a beacon to recruit them to specific sites of inflammatory genes respectively. PTIP deficiency alters H3K27 acetylation state of cis-regulatory elements of inflammatory genes. Moreover, PTIP and c-JUN shape a positive and feedforward regulatory circuit. In addition, PTIP deletion sustains immunosuppressive function of tumor-associated macrophages (TAMs) and promotes tumor growth. Overall, our findings uncover a critical role of PTIP in altering the acetylation state of cis-regulatory regions and fine-tuning the inflammatory responses of innate immune cells.
2022-12-30 | GSE163221 | GEO
Project description:Innate immune cells including myeloid cells exhibit dynamic cellular switches during inflammatory and immune responses against infection. These processes are tightly regulated at different levels including the cis-regulatory elements of immune cells. However, it remains unclear how the dynamic states of cis-regulatory elements of innate immune cells are controlled during inflammatory responses. Here we found that histone methylation regulator PTIP orchestrates inflammatory responses of macrophages through regulating acetylation state of enhancers and promoters. Rapid elevated expression of PTIP is observed in primary human and mouse macrophages upon lipopolysaccharide (LPS) stimulation. Loss of PTIP represses transcription of pro-inflammatory genes, and activates expression of anti-inflammatory genes. Mechanistically, we found that, independent of its function in histone methylation, PTIP interacts with acetyltransferase p300 and deacetylase HDACs, and serves as a beacon to recruit them to specific sites of inflammatory genes respectively. PTIP deficiency alters H3K27 acetylation state of cis-regulatory elements of inflammatory genes. Moreover, PTIP and c-JUN shape a positive and feedforward regulatory circuit. In addition, PTIP deletion sustains immunosuppressive function of tumor-associated macrophages (TAMs) and promotes tumor growth. Overall, our findings uncover a critical role of PTIP in altering the acetylation state of cis-regulatory regions and fine-tuning the inflammatory responses of innate immune cells.
2022-12-30 | GSE163208 | GEO
Project description:Methylation of histone H3 lysine 4 (H3K4me) at actively expressed, cell type-specific genes is established during development by the Trithorax group of epigenetic regulators. In mammals, the Trithorax family includes KMT2A-D (MLL1-4), a family of SET domain proteins that function in large complexes to impart mono-, di-, and trimethylation at H3K4. Individual KMT2s and their co-factors are essential for embryonic development and the establishment of correct gene expression patterns, presumably by demarcating the active and accessible regions of the genome in a cell specific and heritable manner. Despite the importance of H3K4me marks in development, little is known about the importance of histone methylation in maintaining gene expression patterns in fully differentiated and non-dividing cell types. In this report, we utilized an inducible cardiac-specific Cre driver to delete the PTIP protein, a key component of a H3K4me complex, and ask whether this activity is still required to maintain the phenotype of terminally differentiated cardiomyocytes. Our results demonstrate that reducing the H3K4me3 marks is sufficient to alter gene expression patterns and significantly augment systolic heart function. These results clearly show that maintenance of H3K4me3 marks is necessary for the stability of the transcriptional program in differentiated cells. The array we performed allowed us to identify genes that are regulated by PTIP and histone methylation. 8-week-old littermate mice on a mixed C57B6 and B6129 background were utilized. Three mice were on a background with a PTIP floxed allele and a wild type PTIP allele (PTIP+1, PTIP+2, PTIP+3). Three mice had a transgene that expresses a modified estrogen receptor -Cre recombinase fusion protein under the control of a cardiac-specific driver (alpha myosin heavy chain, Jackson Lab stock #005650) and a floxed PTIP allele and a null PTIP (PTIPKO1, PTIPKO2, PTIPKO3). Both groups of mice were injected with tamoxifen at 8 weeks of age. Tamoxifen deletes the floxed PTIP allele in the PTIPKO mice. 5 days after tamoxifen injection, RNA was harvested from left ventricle (LV) apices in both groups. RNA was then sent to the University of Michigan microarray facility core for analysis.
2010-03-06 | E-GEOD-20570 | biostudies-arrayexpress
Project description:Programmed genetic rearrangements in lymphocytes require transcription at antigen receptor genes to promote accessibility for initiating double-strand break (DSB) formation critical for DNA recombination and repair. Here we show that activated B cells deficient in the PTIP component of the MLL3 (mixed-lineage leukemia 3) /MLL4 complex display impaired histone methylation (H3K4me3) and transcription initiation of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus leading to defective immunoglobulin class-switching. We also show that PTIP accumulation at DSBs contributes to class-switch recombination (CSR) and genome stability independently from Igh switch transcription. These results demonstrate that PTIP promotes specific chromatin changes that control the accessibility of the Igh locus to CSR, and suggest a non-redundant role for the MLL3/MLL4 complex in altering antibody effector function. Genome-wide analysis of histone modifications, PTIP, and Pol II in PTIP-WT and PTIP-KO mouse activated B cells.
2010-08-25 | E-GEOD-20852 | biostudies-arrayexpress
Project description:PTIP (Pax2 transactivation domain-interacting protein) is a nuclear protein containing six BRCT domains. It has been shown that PTIP affects gene expression by controlling the activity of the transcription factor Pax2 and histone H3 lysine 4 methyltransferase complexes. In addition to its role in transcriptional regulation, PTIP has been implicated in DNA damage response. To ask if the depletion of PTIP affects the expression level of genes encoding DNA damage response factors , we compared the whole transcripts between wild-type and PTIP deficient chicken DT40 B cell lines.
2009-10-28 | GSE18778 | GEO