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

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

PROVIDER: PRJNA575771 | 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 [RNA-Seq_1]

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 | GSE138415 | GEO

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

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_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

A cyclic peptide toolkit reveals mechanistic principles of peptidylarginine deiminase IV (PADI4) regulation

Project description:Deregulation of the peptidylarginine deiminase PADI4 promotes the development of autoimmunity, cancer, atherosclerosis and age-related tissue fibrosis. Genetic or pharmacological PADI4 inhibition is therapeutically efficacious in mice but no clinically relevant inhibitors exist to date. PADI4 additionally mediates the innate immune response and cellular reprogramming, although the full extent of its physiological roles is not understood. Despite having detailed molecular understanding of PADI4 activation in vitro, we lack understanding of its regulation within cells. Here, we identified a set of potent and selective PADI4 modulators. Using the mRNA-display-based RaPID system, we screened >1012 cyclic peptides for high-affinity, conformation-selective binders of human PADI4. We report PADI4_3, an inhibitor specific for the active conformation; PADI4_7, an inert binder, which we functionalised for the isolation and study of cellular PADI4; and PADI4_11, a first-in-class activator. Using a newly developed method for the quantification of cellular PADI4 activity, we show that PADI4_3 and PADI4_11 can modulate PADI4 activity in cells. Structural studies with PADI4_11 reveal an allosteric binding mode that may reflect the mechanism that promotes activation of PADI4 within cells. This work offers new understanding of PADI4 regulation and a toolkit for the study and modulation of PADI4 across different physiological and pathophysiological contexts.

2025-05-06 | PXD048807 | Pride

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

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

| PRJNA576212 | ENA

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 [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

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