EXPERIMENT_TITLE: GSM4349545: PDX31_CC_SJPHALL008_HiC; Homo sapiens; Hi-C
EXPERIMENT_DESIGN_LIBRARY_DESCRIPTOR_LIBRARY_CONSTRUCTION_PROTOC: Hi-C in GM12878 cells and PDX samples were performed using the Arima-HiC kit as per the manufacturer's instructions. Briefly, 1 million GM12878 WT,  A/A cells and PDX sample  were fixed with 1% formaldehyde, digested with restriction enzyme, end-labeled with Biotin-14-dATP, and then followed by ligation.  The ligated chromatin was reverse-crosslinked and sonicated by Covaris E220 to produce 300–500 bp fragments . Biotin labeled DNA fragments were isolated using dynabeads Streptavidin  C1 beads. To prepare the library, eluted DNA was processed by end repair, adenylation, adaptor ligation, PCR amplification with KAPA DNA library prepare kit. The libraries were sequenced on Illumina HiSeq platform.
STUDY_DESCRIPTOR_STUDY_ABSTRACT: Inherited non-coding genetic variants confer significant disease susceptibility in many cancers. However, the molecular processes by which germline variants contribute to somatic lesions are poorly understood. We performed targeted sequencing in 5,008 patients and identified a key regulatory germline variant in GATA3 strongly associated with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). By creating an isogenic cellular model with a CRISPR-Cas9 system, we showed that this variant activated a strong enhancer that significantly upregulated GATA3 transcription, which in turn reshaped the global chromatin accessibility and 3D genome organization. Remarkably, this genotype switch induced a chromatin loop between the CRLF2 oncogene and a distal enhancer, similar to the somatically acquired super-enhancer hijacking event in patients. GATA3 genotype-related alterations in transcriptional control and 3D chromatin organization were further validated in Ph-like ALL patients. Finally, we showed that GATA3 directly regulates CRLF2 and potentiates the oncogenic effects of JAK-STAT signaling in leukemogenesis. Altogether, our results provide evidence for a novel mechanism by which a germline non-coding variant contributes to oncogene activation epigenetic regulation and 3D genome reprogramming. Overall design: GM12878 cells were engineered to knock in the A allele at rs3824462. Consequences of the epigenetics and chromatin topology change between GM12878 cells/patients(CC) and engineered cells/patients(AA)  were investigated using ChIP-seq, RNA-seq, and Hi-C.
SAMPLE_TITLE: PDX31_CC_SJPHALL008_HiC
SAMPLE_SAMPLE_ATTRIBUTES_SAMPLE_ATTRIBUTE: [{"TAG": "source_name", "VALUE": "Tissue"}, {"TAG": "tissue", "VALUE": "patient-derived xenografts"}]
Pool_Member_@attributes_sample_title: PDX31_CC_SJPHALL008_HiC
RUN_SET_RUN_Pool_Member_@attributes_sample_title: PDX31_CC_SJPHALL008_HiC
RUN_SET_RUN_SRAFiles_SRAFile: [{"Alternatives": [null, null, null], "@attributes": {"cluster": "public", "filename": "SRR11187364.lite", "url": "https://sra-downloadb.be-md.ncbi.nlm.nih.gov/sos4/sra-pub-zq-1/SRR011/11187/SRR11187364/SRR11187364.lite.1", "size": "33484085462", "date": "2022-06-10 16:20:29", "md5": "6db655fdb31ab2f4442cabd2e47bddea", "version": "1", "semantic_name": "SRA Lite", "supertype": "Primary ETL", "sratoolkit": "1"}}, {"Alternatives": null, "@attributes": {"cluster": "public", "filename": "SRR11187364", "url": "https://sra-pub-run-odp.s3.amazonaws.com/sra/SRR11187364/SRR11187364", "size": "42396062886", "date": "2020-02-27 00:21:58", "md5": "b0e3fb939a0c83b73a4faf4bd0706756", "version": "1", "semantic_name": "SRA Normalized", "supertype": "Primary ETL", "sratoolkit": "1"}}, {"Alternatives": null, "@attributes": {"cluster": "public", "filename": "PDX31_CC_SJPHALL008_HiC_R2.fastq.gz", "size": "33523058122", "date": "2020-02-26 23:29:44", "md5": "307454089ab580395bb66f93a11a5345", "version": "1", "semantic_name": "fastq", "supertype": "Original", "sratoolkit": "0"}}, {"Alternatives": null, "@attributes": {"cluster": "public", "filename": "PDX31_CC_SJPHALL008_HiC_R1.fastq.gz", "size": "30938996572", "date": "2020-02-26 23:44:13", "md5": "780a32b806d170fa20e19902a8104882", "version": "1", "semantic_name": "fastq", "supertype": "Original", "sratoolkit": "0"}}]