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Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells

ABSTRACT: Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells

PROVIDER: PRJNA576212 | ENA |

REPOSITORIES: ENA

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Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [Array]

Project description:Peptidylarginine deiminases (PADIs) catalyze post-translational modification of many target proteins and have been suggested to play a role in carcinogenesis. Since citrullination of histones by PADI4 was recently implicated in regulating embryonic stem and hematopoietic progenitor cells, here we investigated a possible role for PADI4 in regulating breast cancer stem cells. We showed by genetic and pharmacologic approaches that PADI4 activity limits the number of cancer stem cells (CSCs) in vitro and in vivo in multiple breast cancer models. A gene signature reflecting tumor cell-autonomous PADI4 inhibition is associated with poor outcome in human breast cancer datasets, consistent with a tumor suppressive role for PADI4. Mechanistically, PADI4 inhibition resulted in a global redistribution of histone H3 with accumulation around transcriptional start sites. Interestingly, epigenetic effects of PADI4 on the bulk tumor cell population did not explain the CSC phenotype. However, in sorted tumor cell populations, PADI4 down-regulated expression of the master transcription factors of stemness, NANOG and POU5F1, specifically in the cancer stem cell compartment, by reducing the transcriptionally activating H3R17me2a histone mark at those loci. This effect was not seen in the non-stem cells. Our findings reveal a novel role for PADI4 as a tumor suppressor in regulating breast cancer stem cells, and provide insights into context-specific effects of PADI4 in epigenetic modulation.

2021-01-11 | GSE138407 | GEO

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [ChIP-Seq]

2021-01-11 | GSE138505 | GEO

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [RNA-Seq_1]

2021-01-11 | GSE138415 | GEO

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [RNA-Seq_2]

2021-01-11 | GSE143442 | GEO

Peptidylarginine deiminase 4 promotes the renal infiltration of neutrophils and exacerbates the TLR7 agonist-induced lupus mice

Project description:Peptidylarginine deiminase 4 (PAD4), encoded by PADI4, plays critical roles in the immune system. The pathological roles of PAD4 were investigated in lupus model mice. PAD4-regulated pathways were identified by RNA-sequencing of WT and Padi4 KO neutrophils.

2020-02-19 | GSE145422 | GEO

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [Array]

Project description:Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [Array]

| PRJNA575748 | ENA

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [RNA-Seq_2]

Project description:Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [RNA-Seq_2]

| PRJNA600506 | ENA

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [RNA-Seq_1]

Project description:Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [RNA-Seq_1]

| PRJNA575771 | ENA

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [ChIP-Seq]

Project description:Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [ChIP-Seq]

| PRJNA576214 | ENA

PADI4 ChIP-chip from MCF-7 cells

Project description:Peptidylarginine deiminase IV (PADI4) catalyzes the conversion of positively charged arginine and methylarginine residues to neutrally charged citrulline residues on histone tails. This activity has been linked to the repression of gene transcription on a limited number of genes. To broaden our knowledge of the regulatory potential of PADI4, we utilized chromatin immunoprecipitation coupled with promoter tiling array (ChIP-chip) to more comprehensively investigate the range of PADI4 target genes across the genome in MCF-7 cells. Results showed that PADI4 is enriched in the gene promoter regions near the transcription start sites (TSSs) and, surprisingly, this pattern of binding is primarily associated with actively transcribed genes. Computational analysis found Elk-1, a member of the ETS oncogene family, to be highly enriched around PADI4 binding sites and coimmunoprecipitation analysis then confirmed that Elk-1 physically associates with PADI4. The expression of two well characterized Elk-1 target genes, c-fos and egr-1, was then found to be inhibited following treatment of MCF-7 cells with a PADI4 specific inhibitor. The inhibitor also significantly reduced levels of acetylation at H4 lysine 5 at these promoters suggesting that the activating function of PADI4 at these target genes is mediated, in part, by interplay between histone citrullination and HAT-mediated acetylation. These findings greatly expand our knowledge of the role of PADI4 in gene regulation by defining a new role for PADI4 catalyzed histone citrullination in mediating gene transactivation. Two PADI4 ChIP-chip biological replicates from MCF-7 human breast cancer cells are included.

2011-03-31 | E-GEOD-18755 | biostudies-arrayexpress

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