(A) Treatment of 4T1 cells with the PAD inhibitor, YW3–56, reduced both hypercitrullination and the formation of CECN. Cells were treated for 15 min with YW3–56 followed by 8 h with A23187. Upper panels: arrow denotes inhibition of CECN formation. H3Cit (red), nuclei (blue). Scale Bar: 50 μm. Lower panels: Quantification of percentage of cells with citrullinated nuclei and/or decondensed chromatin. Data are shown as mean ± SD (n = 8–10 fields from three independent experiments). **p<0.01, ***p<0.001. (B) Chromatograms from Sanger sequencing of the region encompassing mutations on exon 1 (left) and exon 2 (right). Green arrows denote mutations. (C) Knockout of the Padi4 gene in 4T1 cells via CRISPR/Cas9 was verified at protein level by Western blot. (D) Transient transfection of hPAD4 into Padi4 CRISPR cells before 8 h 4 μM A23187 treatment rescued the formation of CECN in 4T1 cells. H3Cit (red), nuclei (blue). Scale Bars: 25 μm. Data shown are representative results from 3 independent transfection experiments.