Altered histone modification between trastuzumab-sensitive and resistant cells.

a, Differential H3K27me3 peaks in JIMT1 and SKBR3 cells. b, Distributions of differential H3K27me3 peaks in JIMT1 and SKBR3 cells. c, Differential H3K4me3 peaks in JIMT1 and SKBR3 cells. d, Distributions of differential H3K4me3 peaks in JIMT1 and SKBR3 cells. e, Distributions of differential RNA polymerase II peaks in JIMT1 and SKBR3 cells. f, Correlationships among differential promoter H3K27me3, H3K4me3, RNA polymerase II enrichments and gene transcription. g, Differential H3K27ac peaks in JIMT1 and SKBR3 cells. h, Distributions of differential H3K27ac peaks in JIMT1 and SKBR3 cells. i, Log2 fold changes of enhancer H3K27ac peaks within ±1Mbp ranges of gene promoters in JIMT1 and SKBR3 cells.

Differential chromatin architecture between trastuzumab-sensitive and resistant cells.

a, Log2 fold changes of intra-chromosomal contacts (JIMT1 vs SKBR3). b, Log2 fold changes of inter-chromosomal contacts (JIMT1 vs SKBR3). c, Detailed intra-chromosomal contacts in a specific chromatin region (Chr8: 58 - 94 kb) of JIMT1 and SKBR3 cells (a indicates JIMT1-specific contacts, b indicates SKBR3-specific contacts). d, Relationship between contact frequency (P) of intra-chromosomal contacts and genome distance (s) in JIMT1 and SKBR3 cells (Top) and the log2 fold changes of frequency ranked by distance (JIMT1 vs SKBR3) (Bottom). The dotted line indicates the crossing point of two curves (∼240 kb). e, The number of chromatin loops in JIMT1 and SKBR3 cells. f, The distributions of loop length in JIMT1 and SKBR3 cells. g, The overall enrichment of the cohesin component Rad21 at the anchors of the chromatin loop in JIMT1 and SKBR3 cells. h, The number of distinct and shared promoter-enhancer chromatin loops in JIMT1 and SKBR3 cells. i, The expression of genes with JIMT1-specific promoter-enhancer chromatin loops. j, The expression of genes with SKBR3-specific promoter-enhancer chromatin loops.

Differential A/B compartments between trastuzumab-sensitive and resistant cells.

a, The distributions of compartment scores at 25 kb genomic bin resolution in JIMT1 and SKBR3 cells. Seven colors represent different categories of bins based on the types of their scores in the two cells (active in JIMT1 / suppressive in SKBR3, suppressive in JIMT1 / active in SKBR3, more active in JIMT1, more active in SKBR3, more suppressive in JIMT1, more suppressive in SKBR3 and stable). b-f, The distributions of log2 histone modifications(H3K27me3, H3K4me3 and H3K27ac), RNA polymerase and gene transcription changes in differential compartment score types in JIMT1 and SKBR3 cells (active in JIMT1 / suppressive in SKBR3, suppressive in JIMT1 / active in SKBR3 and stable).

Altered histone modifications and DNA loops regulate gene transcription.

a, The log2 fold changes of promoter H3K4me3 and RNA polymerase II, and transcription of genes with JIMT1 or SKBR3-specific promoter-enhancer chromatin loops. b, The log2 fold changes of promoter H3K4me3 and RNA polymerase II, and transcription of the SGK1 gene. c, The enrichments of promoter H3K27me3, H3K4me3 and RNA polymerase II, and transcription of SGK1 gene in JIMT1 and SKBR3 cells. d, The chromatin contacts, peaks of Rad21 and H3K27ac, activated enhancer and chromatin loops around SGK1 gene in JIMT1 and SKBR3 cells (red a represents chromatin contacts in both JIMT1 and SKBR3 cells, red b represents SKBR3-specific contacts).

Upregulated SGK1 expression connects trastuzumab resistance.

a, The SGK1 protein level in SGK1- and vector-transfected SKBR3 cells. b, The clone formation abilities of SGK1- and vector-transfected SKBR3 cells. c, The migration abilities of SGK1- and vector-transfected SKBR3 cells. d, The invasive abilities of SGK1- and vector-transfected SKBR3 cells. e, The SGK1 protein level in siSGK1- and control-transfected JIMT1 cells. f, The clone formation abilities of siSGK1- and control-transfected JIMT1 cells. g, The migration abilities of siSGK1- and control-transfected JIMT1 cells. h, The invasive abilities of siSGK1- and control-transfected JIMT1 cells. i, Tumor samples of different treatment strategies. j, The tumor volume changes of different treatment strategies during the experiment.